Novel compounds

ABSTRACT

The invention provides compounds of formula 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 3  and R 4  have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

This application is a 35 USC Section 111(a) continuation of U.S. patentapplication Ser. No. 10/497,744 filed Jun. 3, 2004, which is a nationalstage 35 USC 371 application of PCT/02/02221 filed Dec. 3, 2002, andclaims priority to Swedish Patent Application No. 0104140-9 filed Dec.7, 2001.

The present invention relates to pyrimidine derivatives, a process fortheir preparation, pharmaceutical compositions containing them, aprocess for preparing the pharmaceutical compositions, and their use intherapy.

The insulin-like growth factor (IGF) axis consists of ligands,receptors, binding proteins and proteases. The two ligands, IGF-I andIGF-II, are mitogenic peptides that signal through interaction with thetype 1 insulin-like growth factor receptor (IGF-1R), a hetero-tetramericcell surface receptor. Binding of either ligand stimulates activation ofa tyrosine kinase domain in the intracellular region of the β-chain andresults in phosphorylation of several tyrosine residues resulting in therecruitment and activation of various signaling molecules. Theintracellular domain has been shown to transmit signals for mitogenesis,survival, transformation, and differentiation in cells. The structureand function of the IGF-1R has been reviewed by Adams et al (Cellularand Molecular Life Sciences, 57, 1050-1093, 2000). The IGF-IIR (alsoknown as mannose 6-phosphate receptor) has no such kinase domain anddoes not signal mitogenesis but may act to regulate ligand availabilityat the cell surface, counteracting the effect of the IGF-1R. The IGFbinding proteins (IGFBP) control availability of circulating IGF andrelease of IGF from these can be mediated by proteolytic cleavage. Theseother components of the IGF axis have been reviewed by Collett-Solbergand Cohen (Endocrine, 12, 121-136, 2000).

There is considerable evidence linking IGF signaling with cellulartransformation and the onset and progression of tumours. IGF has beenidentified as the major survival factor that protects from oncogeneinduced cell death (Harrington et al, EMBO J, 13, 3286-3295, 1994).Cells lacking IGF-1R have been shown to be refractory to transformationby several different oncogenes (including SV40T antigen and ras) thatefficiently transform corresponding wild-type cells (Sell et al, Mol.Cell Biol., 14, 3604-12, 1994). Upregulation of components of the IGFaxis has been described in various tumour cell lines and tissues,particularly tumours of the breast (Surmacz, Journal of Mammary GlandBiology & Neoplasia, 5, 95-105, 2000), prostate (Djavan et al, World J.Urol., 19, 225-233, 2001, and O'Brien et al, Urology, 58, 1-7, 2001) andcolon (Guo et al, Gastroenterology, 102, 1101-1108, 1992). Conversely,IGF-IIR has been implicated as a tumour suppressor and is deleted insome cancers (DaCosta et al, Journal of Mammary Gland Biology &Neoplasia, 5, 85-94, 2000). There are a growing number ofepidemiological studies linking increased circulating IGF (or increasedratio of IGF-1 to IGFBP3) with cancer risk (Yu and Rohan, J. Natl.Cancer Inst., 92, 1472-1489, 2000). Transgenic mouse models alsoimplicate IGF signaling in the onset of tumour cell proliferation (Lammand Christofori, Cancer Res. 58, 801-807, 1998, Foster et al, CancerMetas. Rev., 17, 317-324, 1998, and DiGiovanni et al, Proc. Natl. Acad.Sci., 97, 3455-3460, 2000).

Several in vitro and in vivo strategies have provided the proof ofprincipal that inhibition of IGF-1R signaling reverses the transformedphenotype and inhibits tumour cell growth. These include neutralizingantibodies (Kalebic et al Cancer Res., 54, 5531-5534, 1994), antisenseoligonucleotides (Resnicoff et al, Cancer Res., 54, 2218-2222, 1994),triple-helix forming oligonucleotides (Rinninsland et al, Proc. Natl.Acad. Sci., 94, 5854-5859, 1997), antisense mRNA (Nakamura et al, CancerRes., 60, 760-765, 2000) and dominant negative receptors (D'Ambrosio etal., Cancer Res., 56, 4013-4020, 1996). Antisense oligonucleotides haveshown that inhibition of IGF-1R expression results in induction ofapoptosis in cells in vivo (Resnicoff et al, Cancer Res., 55, 2463-2469,1995) and have been taken into man (Resnicoff et al, Proc. Amer. Assoc.Cancer Res., 40 Abs 4816, 1999). However, none of these approaches isparticularly attractive for the treatment of major solid tumour disease.

Since increased IGF signaling is implicated in the growth and survivalof tumour cells, and blocking IGF-1R function can reverse this,inhibition of the IGF-1R tyrosine kinase domain is an appropriatetherapy by which to treat cancer. In vitro and in vivo studies with theuse of dominant-negative IGF-1R variants support this. In particular, apoint mutation in the ATP binding site which blocks receptor tyrosinekinase activity has proved effective in preventing tumour cell growth(Kulik et al, Mol. Cell. Biol., 17, 1595-1606, 1997). Several pieces ofevidence imply that normal cells are less susceptible to apoptosiscaused by inhibition of IGF signaling, indicating that a therapeuticmargin is possible with such treatment (Baserga, Trends Biotechnol., 14,150-2, 1996).

There are few reports of selective IGF-1R tyrosine kinase inhibitors.Parrizas et al. described tyrphostins that had some efficacy in vitroand in vivo (Parrizas et al., Endocrinology, 138:1427-33 (1997)). Thesecompounds were of modest potency and selectivity over the insulinreceptor. Telik Inc. have described heteroaryl-aryl ureas which haveselectivity over insulin receptors but potency against tumour cells invitro is still modest (Published PCT Patent Application No. WO00/35455).

In accordance with the present invention, there is provided a compoundof formula (I):

wherein

R¹ represents a 5- or 6-membered heteroaromatic ring comprising at leastone ring heteroatom selected from nitrogen, oxygen and sulphur, the ringbeing optionally substituted by at least one substituent selected fromC₁-C₆alkyl, C₁-C₆alkoxy (each of which may be optionally substituted byat least one substituent selected from halogen, amino (—NH₂), hydroxyland trifluoromethyl), halogen, nitro, cyano, —NR⁵R⁶, carboxyl, hydroxyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl,C₁-C₆alkylcarbonylamino, phenylcarbonyl, —S(O)_(m)C₁-C₆alkyl,—C(O)NR⁷R⁸, —SO₂NR^(7a)R^(8a), and an unsaturated 5- to 6-membered ringwhich may comprise at least one ring heteroatom selected from nitrogen,oxygen and sulphur, the ring itself being optionally substituted by atleast one substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy (each ofwhich may be optionally substituted by at least one substituent selectedfrom halogen, amino (—NH₂), hydroxyl and trifluoromethyl), halogen,nitro, cyano, —NR⁹R¹⁰, carboxyl, hydroxyl, C₂-C₆alkenyl,C₃-C₆cycloalkyl, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl,C₁-C₆alkylcarbonylamino, phenylcarbonyl, —S(O)_(n)C₁-C₆alkyl,—C(O)NR¹¹R¹² and —SO₂NR^(11a)R^(12a);

m is 0, 1 or 2;

n is 0, 1 or 2;

R² represents a C₁-C₄alkyl group optionally substituted by at least onesubstituent selected from halogen, hydroxyl and C₁-C₃alkoxy;

R³ represents hydrogen, halogen or trifluoromethyl;

R⁴ represents a 5-membered heteroaromatic ring comprising at least onering heteroatom selected from nitrogen, oxygen and sulphur, the ringbeing optionally substituted by at least one substituent selected fromC₁-C₆alkyl, C₁-C₆alkoxy (each of which may be optionally substituted byat least one substituent selected from halogen, amino (—NH₂), hydroxyland trifluoromethyl), halogen, nitro, cyano, —NR¹³R¹⁴, carboxyl,hydroxyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₁-C₄alkoxycarbonyl,C₁-C₄alkylcarbonyl, C₁-C₄alkylcarbonylamino, phenylcarbonyl,—S(O)_(p)C₁-C₄alkyl, —C(O)NR¹⁵R¹⁶ and —SO₂NR^(15a)R^(16a);

p is 0, 1 or 2;

R⁵ and R⁶ each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle;

R⁷ and R⁸ each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R⁷ and R⁸ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle;

R^(7a) and R^(8a) each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R^(7a) and R^(8a) together with the nitrogen atom towhich they are attached form a 4- to 6-membered saturated heterocycle;

R⁹ and R¹⁰ each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R⁹ and R¹⁰ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle;

R¹¹ and R¹² each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R¹¹ and R¹² together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle;

R^(11a) and R^(12a) each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R^(11a) and R^(12a) together with the nitrogen atomto which they are attached form a 4- to 6-membered saturatedheterocycle;

R¹³ and R¹⁴ each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R¹³ and R¹⁴ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle;

R¹⁵ and R¹⁶ each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R¹⁵ and R¹⁶ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle; and

R^(15a) and R^(16a) each independently represent hydrogen, C₁-C₄alkyl orC₃-C₆cycloalkyl, or R^(15a) and R^(16a) together with the nitrogen atomto which they are attached form a 4- to 6-membered saturatedheterocycle;

or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, unless otherwise indicated,an alkyl substituent group or an alkyl moiety in a substituent group maybe linear or branched. When R⁵ and R⁶, or R⁷ and R⁸, or R^(7a) andR^(8a), or R⁹ and R¹⁰, or R¹¹ and R¹², or R^(11a) and R^(12a), or R¹³and R¹⁴, or R¹⁵ and R¹⁶, or R^(15a) and R^(16a) represent a saturatedheterocycle, it should be understood that the only heteroatom present isthe nitrogen atom to which R⁵ and R⁶, or R⁷ and R⁸, or R^(7a) andR^(8a), or R⁹ and R¹⁰, or R¹¹ and R¹², or R^(11a) and R^(12a), or R¹³and R¹⁴, or R¹⁵ and R¹⁶, or R^(15a) and R^(16a) are attached. In thedefinition of R¹, it should be noted that the unsaturated 5- to6-membered ring may have alicyclic or aromatic properties.

Examples of “C₁-C₆alkyl” and “C₁-C₄alkyl” include methyl, ethyl,isopropyl and t-butyl. Examples of “C₁-C₆alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁-C₆alkoxy” and “C₁-C₃alkoxy” include methoxy, ethoxy and propoxy.Examples of “C₁-C₆alkylcarbonylamino” include formamido, acetamido andpropionylamino. Examples of “S(O)_(m)C₁-C₆alkyl” wherein m is 0 to 2include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyland ethylsulphonyl. Examples of “C₁-C₆alkylcarbonyl” include propionyland acetyl. Examples of “C₂-C₆alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₃-C₆cycloalkyl” are cyclopropyl, cyclopentyl andcyclohexyl.

A “5- or 6-membered heteroaromatic ring comprising at least one ringheteroatom selected from nitrogen, oxygen and sulphur” is a fullyunsaturated, aromatic monocyclic ring containing 5 or 6 atoms of whichat least one is a heteroatom selected from nitrogen, oxygen and sulphur,which may, unless otherwise specified, be carbon or nitrogen linked.Suitably a “5- or 6-membered heteroaromatic ring comprising at least onering heteroatom selected from nitrogen, oxygen and sulphur” is pyridyl,imidazolyl, isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyrrolyl or thienyl; said pyridyl, imidazolyl, isoxazolyl,pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl orthienyl.

An “unsaturated 5- to 6-membered ring which may comprise at least onering heteroatom selected from nitrogen, oxygen and sulphur” is a fullyor partially unsaturated, monocyclic ring containing 5 or 6 atomsoptionally of which at least one is a heteroatom selected from nitrogen,oxygen and sulphur, and which may, unless otherwise specified, be carbonor nitrogen linked. Suitably an “unsaturated 5- to 6-membered ring whichmay comprise at least one ring heteroatom selected from nitrogen, oxygenand sulphur” is phenyl or pyridyl.

A “5-membered heteroaromatic ring comprising at least one ringheteroatom selected from nitrogen, oxygen and sulphur” is a fullyunsaturated, aromatic monocyclic ring containing 5 atoms of which atleast one is a heteroatom selected from nitrogen, oxygen and sulphur,which may, unless otherwise specified, be carbon or nitrogen linked.Suitably a “5-membered heteroaromatic ring comprising at least one ringheteroatom selected from nitrogen, oxygen and sulphur” is pyrazolyl.

R¹ represents an optionally substituted 5- or 6-membered heteroaromaticring comprising at least one ring heteroatom (e.g. one, two, three orfour ring heteroatoms independently) selected from nitrogen, oxygen andsulphur. Examples of heteroaromatic rings include thienyl (e.g.3-thienyl), pyrazolyl (e.g. 4-pyrazolyl), isoxazolyl (e.g.5-isoxazolyl), thiadiazolyl, pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or3-furanyl), thiazolyl, triazolyl, tetrazolyl, imidazolyl (e.g.4-imidazolyl), pyrazinyl (e.g. 2-pyrazinyl), pyridazinyl (e.g.3-pyridazinyl), pyrimidinyl (e.g. 4- or 5-pyrimidinyl) and pyridyl (2-,3- or 4-pyridyl).

In R¹, the 5- or 6-membered heteroaromatic ring is optionallysubstituted by at least one substituent (e.g. one, two, three or foursubstituents independently) selected from C₁-C₆, particularly C₁-C₄alkyl(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl), C₁-C₆, particularly C₁-C₄alkoxy (suchas methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy orn-hexoxy) (each of the C₁-C₆alkyl and C₁-C₆alkoxy substituent groupsbeing optionally substituted by at least one substituent, e.g. one, two,three or four substituents independently, selected from halogen (such asfluorine, chlorine bromine or iodine), amino, hydroxyl andtrifluoromethyl), halogen (such as fluorine, chlorine, bromine oriodine), nitro, cyano, —NR⁵R⁶, carboxyl, hydroxyl, C₂-C₆, particularlyC₂-C₄alkenyl (such as ethenyl), C₃-C₆cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), C₁-C₆, particularlyC₁-C₄alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl), C₁-C₆,particularly C₁-C₄alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonylor n-hexylcarbonyl), C₁-C₆, particularly C₁-C₄alkylcarbonylamino (suchas methylcarbonylamino or ethylcarbonylamino), phenylcarbonyl,—S(O)_(m)C₁-C₆, particularly C₁-C₄alkyl, —C(O)NR⁷R⁸, —SO₂NR^(7a)R^(8a),and an optionally substituted unsaturated 5- to 6-membered ring whichmay comprise at least one ring heteroatom (e.g. one, two, three or fourring heteroatoms independently) selected from nitrogen, oxygen andsulphur.

Examples of the unsaturated 5- to 6-membered ring include phenyl,cylopentenyl, cyclohexenyl, thienyl (e.g. 3-thienyl), pyrazolyl (e.g.4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl, pyrrolyl(e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl, triazolyl,tetrazolyl, imidazolyl (e.g. 4-imidazolyl), pyrazinyl (e.g.2-pyrazinyl), pyridazinyl (e.g. 3-pyridazinyl), pyrimidinyl (e.g. 4- or5-pyrimidinyl) and pyridyl (2-, 3- or 4-pyridyl). The ring may itself beoptionally substituted by at least one substituent (e.g. one, two, threeor four substituents independently) selected from C₁-C₆, particularlyC₁-C₄alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆, particularlyC₁-C₄alkoxy (such as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy,n-pentoxy or n-hexoxy) (each of the C₁-C₆alkyl and C₁-C₆alkoxysubstituent groups being optionally substituted by at least onesubstituent, e.g. one, two, three or four substituents independently,selected from halogen (such as fluorine, chlorine bromine or iodine),amino, hydroxyl and trifluoromethyl), halogen (such as fluorine,chlorine, bromine or iodine), nitro, cyano, —NR⁹R¹⁰, carboxyl, hydroxyl,C₂-C₆, particularly C₂-C₄alkenyl (such as ethenyl), C₃-C₆cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C₁-C₆,particularly C₁-C₄alkoxycarbonyl (such as methoxycarbonyl orethoxycarbonyl), C₁-C₆, particularly C₁-C₄alkylcarbonyl (such asmethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆,particularly C₁-C₄alkylcarbonylamino (such as methylcarbonylamino orethylcarbonylamino), phenylcarbonyl, —S(O)_(n)C₁-C₆, particularlyC₁-C₄alkyl, —C(O)NR¹¹R¹² and —SO₂NR^(11a)R^(12a).

Particular values of variable groups are as follows. Such values may beused where appropriate with any of the definitions, claims orembodiments defined hereinbefore or hereinafter.

In one embodiment of the invention, R¹ represents a 5- or 6-memberedheteroaromatic ring comprising one or two ring heteroatoms selected fromnitrogen and oxygen, the ring being optionally substituted by at leastone substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy, halogen, nitro,cyano, —NR⁵R⁶, carboxyl, hydroxyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl,C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl, C₁-C₆alkylcarbonylamino,phenylcarbonyl, —S(O)_(m)C₁-C₆alkyl, —C(O)NR⁷R⁸, —SO₂NR^(7a)R^(8a), andan unsaturated 6-membered ring which may comprise one ring nitrogenatom, the ring itself being optionally substituted by at least onesubstituent selected from C₁-C₆alkyl, C₁-C₆alkoxy, halogen, nitro,cyano, —NR⁹R¹⁰, carboxyl, hydroxyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl,C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl, C₁-C₆alkylcarbonylamino,phenylcarbonyl, —S(O)_(n)C₁-C₆alkyl, —C(O)NR¹¹R¹² and—SO₂NR^(11a)R^(12a).

In a further embodiment of the invention, R¹ represents a 5- or6-membered heteroaromatic ring comprising one or two ring heteroatomsselected from nitrogen and oxygen, the ring being optionally substitutedby at least one substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy,halogen, phenyl and pyridyl, each of the phenyl and pyridyl substituentgroups itself being optionally substituted by at least one substituentselected from C₁-C₆alkyl, C₁-C₆alkoxy and halogen.

In an additional aspect R¹ represents a 5- or 6-membered heteroaromaticring comprising at least one ring heteroatom selected from nitrogen,oxygen and sulphur, the ring being optionally substituted by at leastone substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy (each of which maybe optionally substituted by at least one substituent selected fromhydroxyl), halogen, —C(O)NR⁷R⁸, C₁-C₆alkoxycarbonyl, and an unsaturated5- to 6-membered ring which may comprise at least one ring heteroatomselected from nitrogen and oxygen, the ring itself being optionallysubstituted by at least one substituent selected from C₁-C₆alkyl,C₁-C₆alkoxy (each of which may be optionally substituted by at least onesubstituent selected from halogen), halogen and cyano; wherein R⁷ and R⁸are both hydrogen or R⁷ and R⁸ together with the nitrogen atom to whichthey are attached form a 4- to 6-membered saturated heterocycle.

In a further additional aspect R¹ represents pyridyl, imidazolyl,isoxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl,pyrrolyl or thienyl; said pyridyl, imidazolyl, isoxazolyl, pyrazolyl,furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl and thienyl beingoptionally substituted by at least one substituent selected from methyl,isopropyl, hydroxymethyl, methoxy, chloro, bromo, carbamoyl,methoxycarbonyl, pyrrolidin-1-ylcarbonyl, phenyl and pyridyl; saidphenyl or pyridyl being optionally substituted by at least onesubstituent selected from methyl, trifluoromethyl, methoxy, ethoxy,trifluoromethoxy, fluoro, chloro, bromo and cyano.

In a further additional aspect R¹ represents pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, 2-methoxypyrid-5-yl, 2-cyanopyrid-5-yl, 3-bromopyrid-5-yl,3-(pyrid-2-yl)pyrid-5-yl, 4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl,3-methylpyrid-2-yl, 6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl,imidazol-4-yl, imidazol-5-yl, 3-methylisoxazol-5-yl,5-methylisoxazol-3-yl, 3-isopropylisoxazol-5-yl,3-methoxycarbonylisoxazol-5-yl, 3-(hydroxymethyl)isoxazol-5-yl,3-carbamoylisoxazol-5-yl, 3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-yl,3-phenylisoxazol-5-yl, 3-(pyrid-2-yl)isoxazol-5-yl,3-(2-methoxypyrid-3-yl)isoxazol-5-yl, 3-(2-methoxyphenyl)isoxazol-5-yl,3-(3-methoxyphenyl)isoxazol-5-yl, 3-(2-ethoxyphenyl)isoxazol-5-yl,3-(2-trifluoromethylphenyl)isoxazol-5-yl,3-(2-trifluoromethoxyphenyl)isoxazol-5-yl,3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl,3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl,3-(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl,fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl,pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl.

R² represents a C₁-C₄alkyl group (such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl) optionally substituted by atleast one substituent (e.g. one, two, three or four substituentsindependently) selected from halogen (e.g. fluorine, chlorine, bromineor iodine), hydroxyl and C₁-C₃alkoxy (e.g. methoxy, ethoxy andn-propoxy).

In one embodiment of the invention, R² represents CH₂ or (CH₂)₂.

In a further embodiment R² represents a C₁-C₄alkyl group.

In an additional embodiment R² represents methyl, ethyl and propyl.

R³ represents hydrogen, halogen (e.g. fluorine, chlorine, bromine oriodine) or trifluoromethyl.

In one embodiment of the invention, R³ represents chlorine or bromine.

In a further embodiment R³ represents hydrogen or halogen.

In an additional embodiment R³ represents hydrogen, chloro or bromo.

R⁴ represents an optionally substituted 5-membered heteroaromatic ringcomprising at least one ring heteroatom (e.g. one, two, three or fourring heteroatoms independently) selected from nitrogen, oxygen andsulphur. Examples of rings include thienyl (e.g. 3-thienyl), pyrazolyl(e.g. 4-pyrazolyl), isoxazolyl (e.g. 5-isoxazolyl), thiadiazolyl,pyrrolyl (e.g. 2-pyrrolyl), furanyl (2- or 3-furanyl), thiazolyl,triazolyl, tetrazolyl, imidazolyl (e.g. 4-imidazolyl).

The 5-membered heteroaromatic ring in R⁴ is optionally substituted by atleast one substituent (e.g. one, two, three or four substituentsindependently) selected from C₁-C₆, particularly C₁-C₄alkyl (such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), C₁-C₆, particularly C₁-C₄alkoxy (such as methoxy,ethoxy, n-propoxy, n-butoxy, tert-butoxy, n-pentoxy or n-hexoxy) (eachof the C₁-C₆alkyl and C₁-C₆alkoxy substituent groups being optionallysubstituted by at least one substituent, e.g. one, two, three or foursubstituents independently, selected from halogen (such as fluorine,chlorine bromine or iodine), amino, hydroxyl and trifluoromethyl),halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano,—NR¹³R¹⁴, carboxyl, hydroxyl, C₂-C₆, particularly C₂-C₄alkenyl (such asethenyl), C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl), C₁-C₄, particularly C₁-C₃alkoxycarbonyl (such asmethoxycarbonyl or ethoxycarbonyl), C₁-C₄, particularlyC₁-C₃alkylcarbonyl (such as methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, isopropylcarbonyl or n-butylcarbonyl), C₁-C₄,particularly C₁-C₃alkylcarbonylamino (such as methylcarbonylamino orethylcarbonylamino), phenylcarbonyl, —S(O)_(p)C₁-C₄, particularlyC₁-C₂alkyl, —C(O)NR¹⁵R¹⁶ and —SO₂NR^(15a)R^(16a).

In one embodiment of the invention, R⁴ represents a 5-memberedheteroaromatic ring comprising one or two ring heteroatoms selected fromnitrogen and oxygen, the ring being optionally substituted by at leastone substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy, halogen, nitro,cyano, —NR¹³R¹⁴, carboxyl, hydroxyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl,C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, C₁-C₄alkylcarbonylamino,phenylcarbonyl, —S(O)_(p)C₁-C₄alkyl, —C(O)NR¹⁵R¹⁶ and—SO₂NR^(15a)R^(16a).

In a further embodiment of the invention, R⁴ represents a 5-memberedheteroaromatic ring comprising two ring nitrogen atoms, the ring beingoptionally substituted by at least one substituent selected fromC₁-C₆alkyl, C₁-C₆alkoxy, halogen and C₃-C₆cycloalkyl.

In an additional embodiment R⁴ represents a 5-membered heteroaromaticring comprising at least one ring heteroatom selected from nitrogen, thering being optionally substituted by at least one substituent selectedfrom C₁-C₆alkyl and C₃-C₆cycloalkyl.

In an additional further embodiment R⁴ represents pyrazolyl, the ringbeing optionally substituted by at least one substituent selected frommethyl, ethyl, isopropyl, propyl, t-butyl and cyclopropyl.

In another further embodiment R⁴ represents 5-methylpyrazol-3-yl,5-ethylpyrazol-3-yl, 5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl,5-t-butylpyrazol-3-yl and 5-cyclopropylpyrazol-3-yl.

R⁵ and R⁶ each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R⁵ and R⁶ together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R⁷ and R⁸ each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R⁷ and R⁸ together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R^(7a) and R^(8a) each independently represent hydrogen, C₁-C₄,particularly C₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), or R^(7a) and R^(8a) togetherwith the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

R⁹ and R¹⁰ each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R⁹ and R¹⁰ together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R¹¹ and R¹² each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R¹¹ and R¹² together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R^(11a) and R^(12a) each independently represent hydrogen, C₁-C₄,particularly C₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), or R^(11a) and R^(12a) togetherwith the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

R¹³ and R¹⁴ each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R¹³ and R¹⁴ together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R¹⁵ and R¹⁶ each independently represent hydrogen, C₁-C₄, particularlyC₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), or R¹⁵ and R¹⁶ together with the nitrogenatom to which they are attached form a 4- to 6-membered saturatedheterocycle (such as pyrrolidinyl or piperidinyl).

R^(15a) and R^(16a) each independently represent hydrogen, C₁-C₄,particularly C₁-C₂alkyl (such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl) or C₃-C₆cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl), or R^(15a) and R^(16a) togetherwith the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), and pharmaceutically acceptable salts andsolvates thereof, in which:

R¹ represents a 5- or 6-membered heteroaromatic ring comprising one ortwo ring heteroatoms selected from nitrogen and oxygen, the ring beingoptionally substituted by at least one substituent selected fromC₁-C₃alkyl, pyridyl, and phenyl optionally substituted by methoxy;

R² represents a C₁-C₂alkyl group;

R³ represents chlorine or bromine; and

R⁴ represents pyrazolyl substituted by at least one substituent selectedfrom C₁-C₄alkyl and cyclopropyl.

In a further aspect of the invention, there is provided a compound offormula (I) (as depicted above) wherein:

R¹ represents a 5- or 6-membered heteroaromatic ring comprising at leastone ring heteroatom selected from nitrogen, oxygen and sulphur, the ringbeing optionally substituted by at least one substituent selected fromC₁-C₆alkyl, C₁-C₆alkoxy (each of which may be optionally substituted byat least one substituent selected from hydroxyl), halogen, —C(O)NR⁷R⁸,C₁-C₆alkoxycarbonyl, and an unsaturated 5- to 6-membered ring which maycomprise at least one ring heteroatom selected from nitrogen and oxygen,the ring itself being optionally substituted by at least one substituentselected from C₁-C₆alkyl, C₁-C₆alkoxy (each of which may be optionallysubstituted by at least one substituent selected from halogen), halogenand cyano; wherein R⁷ and R⁸ are both hydrogen or R⁷ and R⁸ togetherwith the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle;

R² represents a C₁-C₄alkyl group;

R³ represents hydrogen or halogen; and

R⁴ represents a 5-membered heteroaromatic ring comprising at least onering heteroatom selected from nitrogen, the ring being optionallysubstituted by at least one substituent selected from C₁-C₆alkyl andC₃-C₆cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

In an additional aspect of the invention, there is provided a compoundof formula (I) (as depicted above) wherein:

R¹ represents pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-methoxypyrid-5-yl,2-cyanopyrid-5-yl, 3-bromopyrid-5-yl, 3-(pyrid-2-yl)pyrid-5-yl,4-(pyrid-2-yl)pyrid-2-yl, 3-chloropyrid-2-yl, 3-methylpyrid-2-yl,6-methylpyrid-2-yl, 5,6-dimethylpyrid-2-yl, imidazol-4-yl,imidazol-5-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl,3-isopropylisoxazol-5-yl, 3-methoxycarbonylisoxazol-5-yl,3-(hydroxymethyl)isoxazol-5-yl, 3-carbamoylisoxazol-5-yl,3-(pyrrolidin-1-ylcarbonyl)isoxazol-5-yl, 3-phenylisoxazol-5-yl,3-(pyrid-2-yl)isoxazol-5-yl, 3-(2-methoxypyrid-3-yl)isoxazol-5-yl,3-(2-methoxyphenyl)isoxazol-5-yl, 3-(3-methoxyphenyl)isoxazol-5-yl,3-(2-ethoxyphenyl)isoxazol-5-yl,3-(2-trifluoromethylphenyl)isoxazol-5-yl,3-(2-trifluoromethoxyphenyl)isoxazol-5-yl,3-(2-chlorophenyl)isoxazol-5-yl, 3-(2-bromophenyl)isoxazol-5-yl,3-(2-methylphenyl)isoxazol-5-yl, 3-(2-fluorophenyl)isoxazol-5-yl,3-(2-cyanophenyl)isoxazol-5-yl, 5-methylpyrazol-4-yl, fur-2-yl,fur-3-yl, 5-methylfur-2-yl, pyrazin-2-yl, 2-methylpyrazin-5-yl,pyridazin-3-yl, pyrimidin-4-yl, 1-methylpyrrol-2-yl and thien-3-yl;

R² represents methyl, ethyl and propyl;

R³ represents hydrogen, chloro or bromo; and

R⁴ represents 5-methylpyrazol-3-yl, 5-ethylpyrazol-3-yl,5-isopropylpyrazol-3-yl, 5-propylpyrazol-3-yl, 5-t-butylpyrazol-3-yl and5-cyclopropylpyrazol-3-yl;

or a pharmaceutically acceptable salt or solvate thereof.

Examples of compounds of the invention include:

-   5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(3-isopropylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(3-phenylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-[3-(2-methoxyphenyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(3-pyrid-2-ylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(pyrid-3-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-(pyrid-2-ylmethylamino)-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-[2-(imidazol-4-ylethyl)amino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(pyrid-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Chloro-2-[2-(pyrid-2-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-[2-(pyrid-3-yl)ethylamino]-4-(5-methyl-1H-pyrazol-3-yamino)pyrimidine,-   5-Bromo-2-(5-methylpyrazin-2-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine,-   5-Bromo-2-(pyrid-3-ylmethylamino)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine,    and pharmaceutically acceptable salts and solvates of any one    thereof.

In a further aspect of the invention, particular compounds of theinvention are any one of Examples 3, 5, 8, 9, 11, 12, 34, 39, 40, 41,47, 48, 68, 70 and 79 or pharmaceutically acceptable salts and solvatesof any one thereof.

In another aspect of the invention, particular compounds of theinvention are any one of the Examples or pharmaceutically acceptablesalts and solvates of any one thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof, which comprises:

(i) reacting a compound of formula

wherein L¹ represents a leaving group (e.g. halogen or sulphonyloxy suchas methanesulphonyloxy or toluene-4-sulphonyloxy) and R³ and R⁴ are asdefined in formula (I), with a compound of formula (III), H₂N—R²—R¹,wherein R¹ and R² are as defined in formula (I); or(ii) reacting a compound of formula

wherein L² represents a leaving group (e.g. halogen or sulphonyloxy suchas methanesulphonyloxy or toluene-4-sulphonyloxy) and R¹, R² and R³ areas defined in formula (I), with a compound of formula (V), H₂N—R⁴,wherein R⁴ is as defined in formula (I); or(iii) reacting a compound of formula

wherein R¹ and R² are as defined in formula (I), with a compound offormula

wherein X represents an oxygen atom and q is 1 or X represents anitrogen atom and q is 2, each R²⁰ independently represents a C₁-C₆alkylgroup and R³ and R⁴ are as defined in formula (I); or(iv) when R⁴ represents a substituted pyrazolyl, reacting a compound offormula

wherein R²¹ represents a C₁-C₆alkyl or C₃-C₆cycloalkyl group and R¹, R²and R³ are as defined in formula (I) with hydrazine;and optionally after (i), (ii), (iii) or (iv) carrying out one or moreof the following:

converting the compound obtained to a further compound of the invention

forming a pharmaceutically acceptable salt or solvate of the compound.

Processes (i) and (ii) may conveniently be carried out as follows:

a) in the presence of a suitable solvent for example a ketone such asacetone or an alcohol such as ethanol or butanol or an aromatichydrocarbon such as toluene or N-methyl pyrrolid-2-one, optionally inthe presence of a suitable acid for example an inorganic acid such ashydrochloric acid or sulphuric acid, or an organic acid such as aceticacid or formic acid (or a suitable Lewis acid) and at a temperature inthe range from 0° C. to reflux, particularly reflux; orb) under standard Buchwald conditions (for example see J. Am. Chem.Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62, 1568and 6066) for example in the presence of palladium acetate, in asuitable solvent for example an aromatic solvent such as toluene,benzene or xylene, with a suitable base for example an inorganic basesuch as caesium carbonate or an organic base such aspotassium-t-butoxide, in the presence of a suitable ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and at a temperature in therange from 25 to 80° C.

Process (iii) may conveniently be carried out in a suitable solvent suchas N-methylpyrrolidinone or butanol at a temperature in the range from100-200° C., in particular in the range from 150-170° C. The reaction ispreferably conducted in the presence of a suitable base such as, forexample, sodium methoxide or potassium carbonate.

Process (iv) may be carried out in a suitable solvent, for example, analcohol such as ethanol or butanol at a temperature in the range from50-120° C., in particular in the range from 70-100° C.

Compounds of formulae (II), (III), (IV), (V), (VI), (VII) and (VIII) areeither commercially available, are known in the literature or may beprepared using known techniques.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. Examples of the types ofconversion reactions that may be used include introduction of asubstituent by means of an aromatic substitution reaction, reduction ofsubstituents, alkylation of substituents and oxidation of substituents.The reagents and reaction conditions for such procedures are well knownin the chemical art. Particular examples of aromatic substitutionreactions include the introduction of a nitro group using concentratednitric acid; the introduction of an acyl group using, for example, anacyl halide and Lewis acid (such as aluminium trichloride) under FriedelCrafts conditions; the introduction of an alkyl group using an alkylhalide and Lewis acid (such as aluminium trichloride) under FriedelCrafts conditions; and the introduction of a halogeno group. Particularexamples of reduction reactions include the reduction of a nitro groupto an amino group by catalytic hydrogenation with a nickel catalyst orby treatment with iron in the presence of hydrochloric acid withheating; and particular examples of oxidation reactions includeoxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at various stages, the additionand removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate, or an alkali metal salt such as a sodium orpotassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers (includingatropisomers) of the compounds of formula (I) and mixtures thereofincluding racemates. The use of tautomers and mixtures thereof also forman aspect of the present invention. For example where R⁴ is pyrazolyl;pyrazolyl-5-yl and pyrazolyl-3-yl are tautomers of the same compound.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators or inhibitors of insulin-like growth factor-1receptor (IGF-1R) activity, and may be used in the treatment ofproliferative and hyperproliferative diseases/conditions, examples ofwhich include the following cancers:

(1) carcinoma, including that of the bladder, brain, breast, colon,kidney, liver, lung, ovary, pancreas, prostate, stomach, cervix, colon,thyroid and skin;(2) hematopoietic tumors of lymphoid lineage, including acutelymphocytic leukaemia, B-cell lymphoma and Burketts lymphoma;(3) hematopoietic tumours of myeloid lineage, including acute andchronic myelogenous leukaemias and promyelocytic leukaemia;(4) tumours of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; and(5) other tumours, including melanoma, seminoma, tetratocarcinoma,neuroblastoma and glioma.

The compounds of the invention are especially useful in the treatment oftumors of the breast and prostate.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating cancer which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined.

The invention still further provides a method of modulating insulin-likegrowth factor-1 receptor (IGF-1R) activity which comprises administeringto a patient in need thereof a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of solutions or suspensions; or bysubcutaneous administration; or by rectal administration in the form ofsuppositories; or transdermally.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30μ or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The size of the dose for therapeutic purposes of a compound of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well known principles of medicine.

In general, a compound of the invention will be administered so that adaily dose in the range, for example, from 0.5 mg to 75 mg activeingredient per kg body weight is received, given if required in divideddoses. In general lower doses will be administered when a parenteralroute is employed. Thus, for example, for intravenous administration, adose in the range, for example, from 0.5 mg to 30 mg active ingredientper kg body weight will generally be used. Similarly, for administrationby inhalation, a dose in the range, for example, from 0.5 mg to 25 mgactive ingredient per kg body weight will generally be used. Oraladministration is however preferred. For example, a formulation intendedfor oral administration to humans will generally contain, for example,from 0.5 mg to 2 g of active ingredient.

For further information on Routes of Administration and Dosage Regimesthe reader is referred to Chapter 25.3 in Volume 5 of ComprehensiveMedicinal Chemistry (Corwin Hansch; Chairman of Editorial Board),Pergamon Press 1990.

EXAMPLES

The invention will now be further described with reference to thefollowing illustrative examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;(ii) organic solutions were dried over anhydrous magnesium sulphate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperatureof up to 60° C.;(iii) chromatography means flash chromatography on silica gel; thinlayer chromatography (TLC) was carried out on silica gel plates;(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;(v) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra and/or mass spectral data;(vi) yields are given for illustration only and are not necessarilythose which can be obtained by diligent process development;preparations were repeated if more material was required;(vii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHz,in DMSO-d₆+CD₃COOD unless otherwise indicated;(viii) chemical symbols have their usual meanings; SI units and symbolsare used;(ix) solvent ratios are given in volume:volume (v/v) terms; and(x) mass spectra were run with an electron energy of 70 electron voltsin the chemical ionization (CI) mode using a direct exposure probe;where indicated ionization was effected by electron impact (EI), fastatom bombardment (FAB) or electrospray (ESP); values for m/z are given;generally, only ions which indicate the parent mass are reported; andunless otherwise stated, the mass ion quoted is (MH)⁺;(xii) the following abbreviations have been used:

THF tetrahydrofuran;

DMF N,N-dimethylformamide;

EtOAc ethyl acetate;

DCM dichloromethane; and

DMSO dimethylsulphoxide.

Example 15-Bromo-2-(3-methylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine

A mixture of 5-aminomethyl-3-methylisoxazole hydrochloride (890 mg, 6.0mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine(Method 1; 578 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.0mmol) in 1-butanol (10 ml) was heated at 120° C. for 18 hours. Themixture was allowed to cool to ambient temperature and volatiles removedby evaporation. The residue was triturated with ether and the productcollected by filtration to give the titled compound (225 mg, 31%). ¹HNMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H), 4.5 (m, 2H), 6.1 (br s, 2H),7.6 (br s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 366.

Examples 2-12

Following a similar procedure to Example 1, the following compounds weresynthesised after replacement with a suitable pyrimidine (SM1) and amine(SM2) (the NMR was recorded in DMSO-d6). Where a starting material isnot indicated, this compound is commercially available.

Ex Compound NMR m/z SM1 SM2  2¹ 5-Chloro-2-(3- 2.15 (s, 3H), 2.20 (s,3H), 320 Meth methylisoxazol-5- 4.45 (d, 2H), 6.2-6.0 (m, 2H), 10ylmethylamino)-4-(5-methyl- 7.6 (br s, 1H), 7.95 (s, 1H), 1H-pyrazol-3-8.5 (br s, 1H), 12.04 (br s, ylamino)pyrimidine 1H)  3^(1,2)5-Bromo-2-(3- 0.6 (br s, 2H), 0.9 (m, 2H), 390 Meth methylisoxazol-5-1.8 (m, 1H), 2.15 (s, 3H), 11 ylmethylamino)-4-(5- 4.5 (m, 2H), 6.0-6.2(br s, 2H), cyclopropyl-1H-pyrazol-3- 8.05 (s, 1H) ylamino)pyrimidine 4¹ 5-Chloro-2-(3- 1.2 (d, 6H), 2.2 (s, 3H), 348 Meth Methisopropylisoxazol-5- 2.9 (m, 1H), 4.5 (m, 2H), 6.2 (br 10 57ylmethylamino)-4-(5-methyl- s, 2H), 7.6 (br s, 1H), 7.98 (s,1H-pyrazol-3- 1H), 12.04 (br s, 1H) ylamino)pyrimidine  5^(1,2)5-Chloro-2-(3- 2.2 (s, 3H), 4.6 (m, 2H), 382 Meth Meth phenylisoxazol-5-6.78 (s, 1H), 7.4 (m, 3H), 7.6 (br s, 10 56 ylmethylamino)-4-(5-methyl-1H), 7.8 (m, 2H), 8.0 (s, 1H), 1H-pyrazol-3- 8.45 (s, 1H), 12.0 (br s,1H) ylamino)pyrimidine  6^(1,2) 5-Bromo-2-[3-(2- 2.2 (s, 3H), 3.8 (s,3H), 456 Meth 1 Meth methoxyphenyl)isoxazol-5- 4.6 (m, 2H), 6.0-6.2 (m,1H), 58 ylmethylamino]-4-(5-methyl- 6.6 (s, 1H), 7.0 (t, 1H), 7.1 (d,1H-pyrazol-3- 1H), 7.45 (m, 1H), 7.7 (s, ylamino)pyrimidine 2H), 8.1 (s,2H), 12.1 (br s, 1H)  7^(1,2) 5-Chloro-2-[3-(2- 2.2 (s, 3H), 3.8 (s,3H), 412 Meth Meth methoxyphenyl)isoxazol-5- 4.5-4.7 (m, 2H), 6.0-6.4(br s, 10 58 ylmethylamino]-4-(5-methyl- 1H), 6.6 (s, 1H), 7.0 (t, 1H),1H-pyrazol-3- 7.15 (d, 1H), 7.45 (m, 1H), ylamino)pyrimidine 7.55-7.7(m, 2H), 8.0 (s, 1H), 8.5 (br s, 1H), 12.05 (s, 1H)  85-Chloro-2-(3-pyrid-2- 2.2 (s, 3H), 4.6 (m, 2H), 383 Meth Methylisoxazol-5-ylmethylamino)- 6.7 (s, 1H), 7.43 (m, 1H), 10 704-(5-methyl-1H-pyrazol-3- 7.63 (br s, 1H), 7.9-8.0 (m, 3H),ylamino)pyrimidine 8.48 (s, 1H), 8.65 (d, 1H), 12.02 (br s, 1H)  9¹5-Bromo-2-(3-pyrid-2- 2.2 (s, 3H), 4.6 (m, 2H), 427 Meth 1 Methylisoxazol-5-ylmethylamino)- 6.0-6.6 (m, 1H), 6.7 (s, 1H), 704-(5-methyl-1H-pyrazol-3- 7.5 (m, 1H), 7.7 (br s, 1H),ylamino)pyrimidine 7.9-8.2 (m, 4H), 8.7 (d, 1H), 12.1 (br s, 1H)10^(1,2) 5-Bromo-2-(3- 1.25 (s, 9H), 2.05 (s, 3H), 406 Methmethylisoxazol-5- 4.50 (d, 2H), 6.05 (s, 1H), 12ylmethylamino)-4-(5-tert- 7.60 (s, 1H), 8.05 (s, 1H),butyl-1H-pyrazol-3- 12.07 (s, 1H) ylamino)pyrimidine 11^(1,2)5-Chloro-2-(3- 1.23 (s, 9H), 2.13 (s, 3H), 362 Meth methylisoxazol-5-4.50 (d, 2H), 6.03 (br s, 1H), 13 ylmethylamino)-4-(5-tert- 6.32 (br s,1H,), 7.55 (br s, butyl-1H-pyrazol-3- 1H), 7.95 (s, 1H), 12.05 (br s,ylamino)pyrimidine 1H) 12² 5-Bromo-2-(3- 1.16 (t, 3H), 2.13 (s, 3H), 378Meth methylisoxazol-5- 2.53 (q, 2H), 4.47 (d, 2H), 14ylmethylamino)-4-(5-ethyl- 6.05 (s, 1H), 7.58 (s, 1H), 1H-pyrazol-3-8.03 (br s, 2H), 12.06 (s, 1H) ylamino)pyrimidine ¹Required aqueouswork-up. ²Purified by column chromatography on silica gel eluting withDCM/methanol (95:5).

Example 135-Bromo-2-(2-fur-2-ylethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine

A mixture of5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1;290 mg, 1.0 mmol), 2-(2-aminoethyl)furan (330 mg, 3.0 mmol) and1-butanol (5 ml) was heated at 120° C. for 5 hours. The mixture wasallowed to cool to ambient temperature and the volatiles removed byevaporation. The residue was dissolved in DCM and washed with waterfollowed by brine. The organics were separated, dried (MgSO₄) and thesolvent removed by evaporation. The residue was triturated with ether,the solid product collected and purified by column chromatography onsilica gel eluting with DCM/methanol (95:5) to give the titled compound(80 mg, 22%). ¹H NMR (DMSO): δ 2.1 (s, 3H), 2.85 (m, 2H), 3.45 (m 2H),6.10 (m, 1H), 6.35 (m, 1H), 6.4 (br s, 1H), 7.15 (br s, 1H), 7.5 (s,1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 363.

Examples 14-106

Following a similar procedure to Example 13, the following compoundswere synthesised after replacement with appropriate pyrimidine (SM1) andamine (SM2) starting materials. Where a starting material is notindicated, this compound is commercially available.

Ex Compound NMR m/z SM1 SM2  14^(1,7) 5-Bromo-2-(pyrid-3- 1.20 (s, 9H),4.50 (d, 2H), 6.05 (s, 402 Meth ylmethylamino)-4-(5- 1H), 7.30 (m, 1H),7.60 (m, 3H), 12 tert-butyl-1H-pyrazol-3- 8.00 (s, 2H), 8.40 (d, 1H),8.45 (s, ylamino)pyrimidine 1H), 12.07 (s, 1H)  15^(2,7)5-Chloro-2-(pyrid-3- 1.19 (s, 9H), 4.47 (d, 2H), 7.28 (t, 358 Methylmethylamino)-4-(5- 1H) 13 tert-butyl-1H-pyrazol-3- ylamino)pyrimidine 16^(2,7) 5-Chloro-2-(pyrid-2- 1.14 (s, 9H), 4.56 (d, 2H), 6.17 (br 358Meth ylmethylamino)-4-(5- s, 1H), 7.61 (s, 1H), 7.69 (t, 1H), 13tert-butyl-1H-pyrazol-3- 7.94 (s, 1H), 8.39 (s, 1H), 8.46 (d,ylamino)pyrimidine 1H), 12.01 (s, 1H)  17^(3,7) 5-Bromo-2-(pyrid-3- 2.17(s, 3H), 4.42 (d, 2H), 360 Meth 1 ylmethylamino)-4-(5- 7.28 (m, 1H), 7.6(m, 2H), 8.0 (br s, methyl-1H-pyrazol-3- 2H), 8.4 (d, 1H), 8.5 (s, 1H),ylamino)pyrimidine 12.01 (br s, 1H)  18^(3,7) 5-Bromo-2-[2-(imidazol-2.2 (s, 3H), 2.75 (t, 2H), 3.45 (m, 363 Meth 1 4-ylethyl)amino]-4-(5-2H), 6.4 (br s, 1H), 6.85 (s, 1H), methyl-1H-pyrazol-3- 7.15 (br s, 1H),7.5 (s, 1H), 8.0 (br ylamino)pyrimidine s, 1H)  19^(4,5,7)5-Bromo-2-(pyrid-2- 2.1 (br s, 3H), 4.5 (d, 2H), 7.2 (m, 360 Meth 1ylmethylamino)-4-(5- 2H), 7.6 (br s, 1H), 7.7 (m, 1H),methyl-1H-pyrazol-3- 7.9 (s, 1H), 8.0 (s, 1H), 8.5 (d,ylamino)pyrimidine 1H), 11.97 (br s, 1H)  20⁷ 5-Chloro-2-[2-(pyrid-2-2.15 (s, 3H), 2.95 (m, 2H), 3.6 (m, 330 Meth yl)ethylamino]-4-(5- 2H),6.5 (s, 1H), 7.05 (br s, 1H), 10 methyl-1H-pyrazol-3- 7.2 (m, 2H), 7.65(t, 1H), 7.9 (s, ylamino)pyrimidine 1H), 8.3 (br s, 1H), 8.5 (m, 1H),12.02 (br s, 1H)  21^(4,5,7) 5-Bromo-2-[2-(pyrid-3- 2.1 (br s, 3H), 2.9(t, 2H), 3.5 (t, 374 Meth 1 yl)ethylamino]-4-(5- 2H), 6.4 (s, 1H), 6.95(t, 1H), methyl-1H-pyrazol-3- 7.05 (t, 1H), 7.1 (s, 1H), 7.3 (d, 1H),ylamino)pyrimidine 7.5 (m, 1H), 8.0 (s, 1H)  22^(4,5,6,7) 5-Bromo-2-(5-2.2 (s, 3H), 2.45 (s, 3H), 4.6 (d, 375 Meth 1 methylpyrazin-2- 2H), 6.2(s, 1H), 7.15 (br s, 1H), ylmethylamino)-4-(5- 8.0 (s, 1H), 8.4 (s, 1H),8.43 (s, methyl-1H-pyrazol-3- 1H) ylamino)pyrimidine  23⁷5-Bromo-2-(pyrid-3- 0.4-0.9 (m, 4H), 1.8 (br s, 1H), 386 Methylmethylamino)-4-(5- 4.4 (m, 2H), 5.8-6.5 (m, 1H), 7.3 (m, 11cyclopropyl-1H-pyrazol- 1H), 7.6 (br s, 2H), 8.0 (s, 2H),3-ylamino)pyrimidine 8.4 (m, 1H), 8.5 (s, 1H), 12.1-12.3 (m, 1H)  245-Bromo-2-[3-(2- 2.19 (s, 3H), 4.64 (s, 2H), 5.74 (s, 460 Meth 1 Methchlorophenyl)isoxazol-5- 1H), 6.18 (br s, 1H), 6.64 (s, 1H), 59ylmethylamino]-4-(5- 7.41-7.55 (m, 2H), 7.74 (t, 1H),methyl-1H-pyrazol-3- 8.07 (s, 1H) ylamino)pyrimidine  255-Bromo-2-[3-(2- 1.21 (s, 9H), 4.67 (s, 2H), 6.31 (br 502 Meth Methchlorophenyl)isoxazol-5- s, 1H), 6.60 (br s, 1H), 12 59ylmethylamino]-4-(5- 7.39-7.54 (m, 2H), 7.56-7.66 (m, 2H),tert-butyl-1H-pyrazol-3- 8.07 (s, 1H) ylamino)pyrimidine  264-(5-Methyl-1H-pyrazol- 2.12 (s, 3H), 4.46 (s, 2H), 6.05 (br 282 Meth3-ylamino)-2-(pyrid-3- s, 1H), 6.21 (br s, 1H), 15 ylmethylamino)-7.26-7.35 (m, 2H), 7.70 (d, 1H), 7.79 (d, pyrimidine 1H), 8.39 (s, 1H),8.55 (s, 1H)  27 5-Bromo-2-[2-(3- 2.18 (s, 6H), 2.96 (t, 2H), 3.51 (t,378 Meth 1 Meth methylisoxazol-5- 2H), 6.12 (s, 1H), 6.36 (s, 1H), 83yl)ethylamino]-4-(5- 8.02 (s, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine  28 5-Chloro-2-[3-(2- 1.21 (s, 9H), 4.65 (s, 2H),6.31 (br 458 Meth Meth chlorophenyl)isoxazol-5- s, 1H), 6.60 (br s, 1H),13 59 ylmethylamino]-4-(5- 7.39-7.52 (m, 2H), 7.57-7.65 (m, 2H),tert-butyl-1H-pyrazol-3- 7.99 (s, 1H) ylamino)pyrimidine  295-Chloro-4-(5-propyl- 0.88 (t, 3H), 1.50 (br s, 2H), 344 Meth1H-pyrazol-3-ylamino)- 2.44 (br s, 2H), 4.53 (s, 2H), 5.87 (br s, 162-(pyrid-2- 1H), 7.16-7.29 (m, 2H), 7.70 (t, ylmethylamino)- H), 7.94(s, 1H), 8.48 (d, 1H) pyrimidine  30 5-Bromo-4-(5- 0.60 (br s, 2H), 0.89(d, 2H), 386 Meth cyclopropyl-1H-pyrazol- 1.78 (br s, 1H), 4.51 (s, 2H),5.87 (br s, 11 3-ylamino)-2-(pyrid-2- 1H), 7.16-7.31 (m, 2H), 7.69 (t,ylmethylamino)- 1H), 8.01 (s, 1H), 8.49 (d, 1H) pyrimidine  315-Chloro-4-(5-ethyl-1H- 1.10 (br s, 3H), 2.44 (br s, 2H), 330 Methpyrazol-3-ylamino)-2- 4.49 (s, 2H), 6.01 (br s, 1H), 17(pyrid-2-ylmethylamino)- 7.17-7.29 (m, 2H), 7.70 (t, 1H), 7.93 (s,pyrimidine 1H), 8.49 (d, 1H)  32 5-Bromo-4-(5-ethyl-1H- 1.10 (br s, 3H),2.54 (br s, 2H), 374 Meth pyrazol-3-ylamino)-2- 4.54 (s, 2H), 6.00 (brs, 1H), 14 (pyrid-2-ylmethylamino)- 7.17-7.30 (m, 2H), 7.69 (t, 1H),7.99 (s, pyrimidine 1H), 8.49 (d, 1H)  33⁷ 5-Bromo-4-(5-propyl- 0.88 (brs, 3H), 1.51 (br s, 2H), 388 Meth 1H-pyrazol-3-ylamino)- 2.45 (br s,2H), 4.55 (s, 2H), 18 2-(pyrid-2- 5.98 (br s, 1H), 7.15-7.30 (m, 2H),ylmethylamino)- 7.59 (s, 1H), 7.72 (t, 1H), 7.95 (s, 1H), pyrimidine8.01 (s, 1H), 8.50 (d, 1H), 11.98 (s, 1H)  34⁷ 5-Chloro-2-[3-(2- 2.19(s, 3H), 4.61 (s, 2H), 6.21 (br 400 Meth Meth fluorophenyl)isoxazol-5-s, 1H), 6.66 (s, 1H), 7.27-7.40 (m, 10 60 ylmethylamino]-4-(5- 2H),7.50-7.60 (m, 1H), 7.66 (br s, methyl-1H-pyrazol-3- 1H), 7.86 (t, 1H),7.99 (s, 1H), ylamino)pyrimidine 8.50 (br s, 1H), 12.04 (s, 1H)  355-Chloro-4-(5-isopropyl- 1.15 (br s, 6H), 2.81 (br s, 1H), 344 Meth1H-pyrazol-3-ylamino)- 4.55 (s, 2H), 6.20 (br s, 1H), 19 2-(pyrid-2-7.15-7.32 (m, 2H), 7.71 (t, 1H), 7.95 (s, ylmethylamino)- 1H), 8.46 (d,1H) pyrimidine  36⁷ 5-Bromo-4-(5-tert-butyl- 1.26 (s, 9H), 4.65 (s, 2H),6.28 (br 552 Meth Meth 1H-pyrazol-3-ylamino)- s, 1H), 6.56 (br s, 1H),12 61 2-[3-(2- 7.46-7.56 (m, 2H), 7.62-7.66 (m, 1H),trifluoromethoxyphenyl)- 7.72 (br s, 1H), 7.85 (d, 1H), 8.05 (s,isoxazol-5- 1H), 12.06 (s, 1H) ylmethylamino]- pyrimidine  375-Chloro-4-(5- 0.60 (br s, 2H), 0.88 (d, 2H), 342 Methcyclopropyl-1H-pyrazol- 1.78 (br s, 1H), 4.52 (s, 2H), 5.95 (br s, 203-ylamino)-2-(pyrid-2- 1H), 7.16-7.31 (m, 2H), 7.69 (t, ylmethylamino)-1H), 7.91 (s, 1H), 8.50 (d, 1H) pyrimidine  38⁸ 5-Chloro-2-[3-(2- 2.18(s, 3H), 4.68 (s, 2H), 6.27 (s, 407 Meth Meth cyanophenyl)isoxazol-5-1H), 6.77 (s, 1H), 7.64 (dt, 1H), 10 81 ylmethylamino]-4-(5- 7.77 (dt,1H), 7.84 (dd, 1H), methyl-1H-pyrazol-3- 7.90 (dd, 1H), 7.96 (s, 1H)ylamino)pyrimidine  39 5-Bromo-2-[3-(2- 2.19 (s, 3H), 4.63 (s, 2H), 6.27(br 444 Meth 1 Meth fluorophenyl)isoxazol-5- s, 1H), 6.66 (s, 1H),7.30-7.44 (m, 60 ylmethylamino]-4-(5- 2H), 7.50-7.61 (m, 1H), 7.87 (t,methyl-1H-pyrazol-3- 1H), 8.09 (s, 1H) ylamino)pyrimidine  40⁷5-Chloro-2-[3-(2- 1.22 (s, 9H), 4.67 (s, 2H), 6.38 (br 442 Meth Methfluorophenyl)isoxazol-5- s, 1H), 6.64 (br s, 1H), 13 60ylmethylamino]-4-(5- 7.28-7.41 (m, 2H), 7.50-7.59 (m, 1H),tert-butyl-1H-pyrazol-3- 7.69 (br s, 1H), 7.85 (t, 1H), 8.00 (s,ylamino)pyrimidine 1H), 8.54 (br s, 1H), 12.10 (s, 1H)  415-Bromo-4-(5-isopropyl- 1.01-1.25 (m, 6H), 2.84 (br s, 1H), 388 Meth1H-pyrazol-3-ylamino)- 4.56 (s, 2H), 6.12 (br s, 1H), 21 2-(pyrid-2-7.19-7.34 (m, 2H), 7.72 (t, 1H), 8.04 (s, ylmethylamino)- 1H), 8.49 (d,1H) pyrimidine  42⁷ 5-Bromo-2-[3-(2- 1.22 (s, 9H), 4.66 (s, 2H), 6.34(br 486 Meth Meth fluorophenyl)isoxazol-5- s, 1H), 6.62 (br s, 1H), 1260 ylmethylamino]-4-(5- 7.28-7.43 (m, 2H), 7.51-7.61 (m, 1H),tert-butyl-1H-pyrazol-3- 7.72 (br s, 1H), 7.86 (t, 1H),ylamino)pyrimidine 8.01-8.18 (br s, 2H), 12.10 (s, 1H)  43⁸5-Bromo-2-[3-(2- 1.69 (s, 3H), 4.20 (s, 2H), 5.78 (s, 451 Meth 1 Methcyanophenyl)isoxazol-5- 1H), 6.27 (s, 1H), 7.15 (dt, 1H), 81ylmethylamino]-4-(5- 7.28 (dt, 1H), 7.35 (dd, 1H) methyl-1H-pyrazol-3-7.41 (dd, 1H), 7.55 (s, 1H) ylamino)pyrimidine  44⁹ 5-Bromo-2-[1-(3-1.50 (s, 3H), 2.18 (s, 3H), 2.22 (s, 378 Meth 1 Meth methylisoxazol-5-3H), 5.18 (q, H), 6.10 (s, H), 72 yl)ethylamino]-4-(5- 6.23 (br s, H),7.68 (br s, H), 8.09 (s, methyl-1H-pyrazol-3- H), 8.53 (br s, H)ylamino)pyrimidine  45⁹ 5-Chloro-2-[1-(3- 1.50 (s, 3H), 2.15 (s, 3H),2.24 (s, 334 Meth Meth methylisoxazol-5- 3H), 5.18 (q, H), 6.10 (s, H),10 72 yl)ethylamino]-4-(5- 6.21 (br s, H), 7.73 (br s, H), 8.01 (s,methyl-1H-pyrazol-3- H), 8.99 (br s, H) ylamino)pyrimidine  46⁷5-Bromo-4-(5-ethyl-1H- 1.10 (t, 3H), 2.54 (q, 2H), 4.42 (d, 374 Methpyrazol-3-ylamino)-2- 2H), 7.26 (t, 1H), 7.50-7.68 (m, 14(pyrid-3-ylmethylamino)- 2H), 7.92-8.05 (m, 2H), 8.37 (d, pyrimidine1H), 8.45 (s, 1H), 12.04 (br s, 1H)  47 5-Bromo-2-(3- 0.85 (t, 3H), 1.58(m, 2H), 2.10 (s, 392 Meth methylisoxazol-5- 3H), 2.50 (t, 2H), 4.50 (s,2H), 18 ylmethylamino)-4-(5- 6.05 (s, 1H), 8.00 (s, 1H)propyl-1H-pyrazol-3- ylamino)pyrimidine  48 5-Bromo-2-(3- 1.18 (d, 6H),2.10 (s, 3H), 392 Meth methylisoxazol-5- 2.85 (m, 1H), 4.5 (s, 2H), 6.00(s, 1H), 21 ylmethylamino)-4-(5- 6.30 (br s, 1H), 8.00 (s, 1H)isopropyl-1H-pyrazol-3- ylamino)pyrimidine  49 5-Bromo-2-[3-(2- 1.25 (brs, 12H), 4.04 (q, 2H), 512 Meth Meth ethoxyphenyl)isoxazol-5- 4.62 (s,2H), 6.35 (br s, 1H), 12 62 ylmethylamino]-4-(5- 6.65 (s, 1H), 7.00 (t,1H), 7.10 (d, 1H), tert-butyl-1H-pyrazol-3- 7.40 (t, 1H), 7.70 (d, 1H),8.07 (s, ylamino)pyrimidine 1H)  50 5-Bromo-4-(5-tert-butyl- 1.30 (s,9H), 4.75 (s, 2H), 6.35 (br 536 Meth Meth 1H-pyrazol-3-ylamino)- s, 1H),6.43 (br s, 1H), 7.58 (d, 12 63 2-[3-(2- 1H), 7.75 (m, 2H), 7.87 (d,1H), trifluoromethylphenyl)- 8.20 (s, 1H) isoxazol-5- ylmethylamino]-pyrimidine  51 5-Bromo-2-[3-(2- 1.23 (s, 9H), 2.36 (s, 3H), 4.65 (s, 482Meth Meth methylphenyl)isoxazol- 2H), 6.36 (br s, 1H), 6.54 (br s, 12 645-ylmethylamino]-4-(5- 1H), 7.32 (m, 3H), 7.44 (d, 1H),tert-butyl-1H-pyrazol-3- 8.20 (s, 1H) ylamino)pyrimidine  52⁷5-Bromo-2-[2- 1.19 (br s, 9H), 3.19 (t, 2H), 417 Meth J Am (pyridazin-3-3.65 (q, 2H), 6.41 (br s, 1H), 7.54 (m, 12 Chemyl)ethylamino]-4-(5-tert- 2H), 7.98 (s, 1H), 9.06 (d, 1H) Soc,butyl-1H-pyrazol-3- 1950, ylamino)pyrimidine 72, 3539  535-Bromo-2-[3-(2- 2.18 (s, 3H), 4.63 (s, 2H), 6.3 (bd, 506 Meth 1 Methbromophenyl)isoxazol-5- 1H), 6.62 (br s, 1H), 7.49 (m, 3H), 65ylmethylamino]-4-(5- 7.76 (d, 1H), 8.07 (s, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine  54 5-Bromo-2-[2- 1.19 (s, 9H), 2.98 (t, 2H), 3.62(q, 417 Meth J Am (pyrimidin-4- 2H), 6.36 (s, 1H), 7.37 (d, 1H), 12 Chemyl)ethylamino]-4-(5-tert- 8.13 (s, 1H), 8.62 (d, 1H), 9.04 (s, Soc,butyl-1H-pyrazol-3- 1H) 1950, ylamino)pyrimidine 72, 3539  55⁷5-Bromo-2-(pyrazin-2- 1.19 (s, 9H), 4.57 (d, 2H), 6.16 (br 403 Methylmethylamino)-4-(5- s, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 12tert-butyl-1H-pyrazol-3- 8.52 (s, 2H) ylamino)pyrimidine  565-Bromo-2-(5- 1.24 (s, 9H), 2.38 (s, 3H), 4.43 (s, 406 Meth Methmethylisoxazol-3- 2H), 6.07 (s, 1H), 6.41 (s, 1H), 12 85ylmethylamino)-4-(5- 8.04 (s, 1H) tert-butyl-1H-pyrazol-3-ylamino)pyrimidine  57⁷ 5-Bromo-2-(pyrid-3- 0.86 (t, 3H), 1.52 (m, 2H),388 Meth ylmethylamino)-4-(5- 2.47 (m, 2H), 4.45 (d, 2H), 6.04 (br s, 18propyl-1H-pyrazol-3- 1H), 7.29 (t, 1H), 7.60 (bt, 1H),ylamino)pyrimidine 8.00 (s, 1H), 8.39 (d, 1H), 8.48 (s, 1H)  585-Bromo-4-(5-isopropyl- 1.14 (s, 6H), 2.84 (m, 1H), 388 Meth1H-pyrazol-3-ylamino)- 4.46 (s, 2H), 6.18 (br s, 1H), 7.28 (t, 212-(pyrid-3- 1H), 7.63 (bt, 1H), 8.00 (s, 1H), ylmethylamino)- 8.38 (d,1H), 8.47 (s, 1H) pyrimidine  59 5-Bromo-2-[3-(2- 2.19 (s, 3H), 3.93 (s,3H), 4.62 (s, 457 Meth 1 Meth methoxypyrid-3- 2H), 6.30 (br s, 1H), 6.70(s, 1H), 66 yl)isoxazol-5- 7.12 (dd, 1H), 8.07 (s, 1H),ylmethylamino]-4-(5- 8.14 (dd, 1H), 8.29 (dd, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine  60⁷ 5-Bromo-2-[3-(3- 1.25 (s, 9H), 1.71 (m, 2H), 433Meth methylpyrazol-4- 2.06 (s, 3H), 2.34 (m, 2H), 3.24 (m, 12yl)propylamino]-4-(5- 2H), 6.47 (br s, 1H), 7.05 (br s,tert-butyl-1H-pyrazol-3- 1H), 7.30 (br s, 1H), 7.97 (s, 1H),ylamino)pyrimidine 12.06 (br s, 1H)  61⁷ 5-Bromo-2-[3-(3- 1.70 (m, 2H),2.08 (s, 3H), 391 Meth 1 methylpyrazol-4- 2.18 (s, 3H), 2.36 (t, 2H),3.20 (m, yl)propylamino]-4-(5- 2H), 6.40 (br s, 1H), 7.03 (br s,methyl-1H-pyrazol-3- 1H), 7.26 (s, 1H), 7.97 (s, 2H), ylamino)pyrimidine12.04 (s, 1H)  62 5-Chloro-4-(5-methyl- 2.12 (s, 3H), 4.5 (d, 2H), 316Meth 1H-pyrazol-3-ylamino)- 7.07-7.36 (m, 2H), 7.51 (br s, 1H), 102-(pyrid-2- 7.67 (m, 1H), 7.91 (s, 1H), 8.34 (s, ylmethylamino)- 1H),8.48 (d, 1H), 11.96 (br s, 1H) pyrimidine  63 5-Chloro-4-(5-methyl- 2.15(s, 3H), 4.43 (m, 2H), 316 Meth 1H-pyrazol-3-ylamino)- 7.29 (s, 1H),7.43-7.74 (m, 2H), 10 2-(pyrid-3- 7.92 (br s, 1H), 8.23-8.56 (m, 3H),ylmethylamino)- 12.0 (br s, 1H) pyrimidine  64 5-Bromo-4-(5-methyl- 2.13(s, 3H), 4.43 (d, 2H), 7.24 (d, 360 Meth 1 1H-pyrazol-3-ylamino)- 2H),7.63 (br s, 1H), 7.99 (s, 2H), 2-(pyrid-4- 8.44 (d, 2H), 11.99 (br s,1H) ylmethylamino)- pyrimidine  65 5-Chloro-2-[2-(imidazol- 2.15 (s,3H), 2.74 (m, 2H), 319 Meth 5-yl)ethylamino]-4-(5- 3.43 (m, 2H), 6.48(br s, 1H), 6.77 (br 10 methyl-1H-pyrazol-3- s, 1H), 7.01 (br s, 1H),7.5 (s, 1H), ylamino)pyrimidine 7.9 (br s, 1H), 8.31 (br s, 1H),11.6-12.1 (m, 2H)  66 5-Chloro-2-[3-(3- 2.19 (s, 3H), 3.81 (s, 3H), 4.61(s, 412 Meth Meth methoxyphenyl)isoxazol- 2H), 6.05-6.45 (m, 1H), 6.81(s, 10 67 5-ylmethylamino]-4-(5- 1H), 7.03 (m, 1H), 7.36-7.40 (m,methyl-1H-pyrazol-3- 4H), 7.99 (s, 1H) ylamino)pyrimidine  675-Chloro-4-(5-methyl- 2.16 (s, 3H), 4.60 (s, 2H), 383 Meth Meth1H-pyrazol-3-ylamino)- 5.97-6.43 (m, 1H), 6.88 (br s, 1H), 10 682-[3-(pyrid-3- 7.49 (m, 1H), 7.96 (s, 1H), 8.20 (m, yl)isoxazol-5- 1H),8.64 (m, 1H), 9.0 (br s, 1H) ylmethylamino]- pyrimidine  685-Chloro-2-[3-(pyrid-2- 1.24 (s, 9H), 4.66 (s, 2H), 6.34 (br 425 MethMeth yl)isoxazol-5- s, 1H), 6.73 (br s, 1H), 7.48 (t, 13 70ylmethylamino]-4-(5- 1H), 7.89-7.99 (m, 3H), 8.65 (d,tert-butyl-1H-pyrazol-3- 1H) ylamino)pyrimidine  69 5-Bromo-4-(5-propyl-0.85 (br s, 3H), 1.55 (br s, 2H), 455 Meth Meth 1H-pyrazol-3-ylamino)-2.5 (2H, m), 4.63 (s, 2H), 18 70 2-[3-(pyrid-2- 6.05-6.52 (m, 1H), 6.74(br s, 1H), yl)isoxazol-5- 7.47 (t, 1H), 7.88-7.99 (m, 2H),ylmethylamino]- 8.07 (s, 1H), 8.66 (d, 1H) pyrimidine  705-Bromo-2-[3-(pyrid-2- 1.23 (s, 9H), 4.66 (s, 2H), 6.34 (br 469 MethMeth yl)isoxazol-5- s, 1H), 6.73 (br s, 1H), 7.48 (m, 12 70ylmethylamino]-4-(5- 1H), 7.86-8.02 (m, 2H), 8.08 (s,tert-butyl-1H-pyrazol-3- 1H), 8.65 (d, 1H) ylamino)pyrimidine  715-Bromo-4-(5-ethyl-1H- 1.15 (m, 3H), 2.54 (m, 2H), 441 Meth Methpyrazol-3-ylamino)-2-[3- 4.64 (s, 2H), 6.05-6.53 (br s, 1H), 14 70(pyrid-2-yl)isoxazol-5- 6.74 (br s, 1H), 7.46 (m, 1H), ylmethylamino]-7.84-8.02 (m, 2H), 8.07 (s, 1H), 8.65 (d, 1H) pyrimidine  725-Bromo-4-(5-isopropyl- 1.17 (m, 6H), 2.80-2.95 (m, 1H), 455 Meth Meth1H-pyrazol-3-ylamino)- 4.64 (br s, 1H), 6.18-6.48 (br s, 21 702-[3-(pyrid-2- 1H), 6.73 (br s, 1H), 7.46 (m, 1H), yl)isoxazol-5-7.82-8.00 (m, 2H), 8.07 (s, 1H), ylmethylamino]- 8.64 (d, 1H) pyrimidine 73¹⁰ 5-Bromo-2-(5-methylfur- 1.24 (s, 9H), 2.21 (s, 3H), 4.48 (s, 405Meth 2-ylmethylamino)-4-(5- 2H), 5.97 (s, 1H), 6.06 (br s, 1H), 12tert-butyl-1H-pyrazol-3- 6.40 (br s, 1H), 8.32 (s, 1H)ylamino)pyrimidine  74¹⁰ 5-Bromo-2-(fur-3- 2.25 (s, 3H), 4.37 (s, 2H),6.24 (s, 349 Meth 1 ylmethylamino)-4-(5- 1H), 6.47 (s, 1H), 7.52 (s,1H), methyl-1H-pyrazol-3- 7.61 (s, 1H), 8.35 (s, 1H) ylamino)pyrimidine 75¹⁰ 5-Bromo-2-(2- 1.15 (s, 9H), 4.62 (s, 2H), 6.05 (s, 427 Meth WOcyanopyrid-5- 1H), 7.86 (m, 1H), 7.93 (d, 1H), 12 02/ylmethylamino)-4-(5- 8.38 (s, 1H), 8.60 (s, 1H) 44145tert-butyl-1H-pyrazol-3- ylamino)pyrimidine  76¹⁰ 5-Bromo-2-(pyrid-2-1.19 (s, 9H), 4.87 (s, 2H), 6.04 (s, 402 Meth ylmethylamino)-4-(5- 1H),7.90 (m, 2H), 8.46 (m, 2H), 12 tert-butyl-1H-pyrazol-3- 8.83 (d, 1H)ylamino)pyrimidine  77¹⁰ 5-Bromo-2-(fur-3- 1.24 (s, 9H), 4.40 (s, 2H),6.36 (br 391 Meth ylmethylamino)-4-(5- s, 1H), 6.43 (br s, 1H), 7.48 (brs, 12 tert-butyl-1H-pyrazol-3- 1H), 7.57 (br s, 1H), 8.35 (s, 1H)ylamino)pyrimidine  78¹⁰ 5-Bromo-2-(2- 1.21 (s, 9H), 3.92 (s, 3H), 4.72(s, 432 Meth WO methoxypyrid-5- 2H), 6.16 (s, 1H), 7.61 (m, 1H), 12 95/ylmethylamino)-4-(5- 7.83 (d, 1H), 8.45 (m, 2H) 18097tert-butyl-1H-pyrazol-3- ylamino)pyrimidine  79¹⁰ 5-Bromo-2-(3- 1.17 (s,9H), 4.60 (s, 2H), 6.13 (s, 480 Meth WO bromopyrid-5- 1H), 8.10 (s, 1H),8.38 (s, 1H), 12 99/ ylmethylamino)-4-(5- 8.52 (s, 1H), 8.70 (s, 1H)00385 tert-butyl-1H-pyrazol-3- ylamino)pyrimidine  80¹⁰5-Bromo-2-(fur-2- 1.24 (s, 9H), 4.56 (s, 2H), 6.21 (s, 391 Methylmethylamino)-4-(5- 1H), 6.39 (br s, 2H), 7.59 (s, 1H), 12tert-butyl-1H-pyrazol-3- 8.34 (s, 1H) ylamino)pyrimidine  81¹⁰5-Bromo-4-(5-methyl- 2.21 (s, 3H), 2.88 (m, 2H), 379 Meth 11H-pyrazol-3-ylamino)- 3.57 (m, 2H), 6.34 (s, 1H), 6.97 (br s,2-[2-(thien-3- 1H), 7.20 (br s, 1H), 7.49 (m, 1H), yl)ethylamino]- 8.33(s, 1H) pyrimidine  82⁷ 5-Bromo-2-[2-(1- 2.10 (m, 3H), 2.75 (t, 2H), 376Meth 1 Tetrahedron methylpyrrol-2- 3.3-3.4 (m, 5H), 5.80 (s, 1H), 5.87(s, 1999, yl)ethylamino]-4-(5- 1H), 6.37 (m, 1H), 6.60 (s, 1H), 55,methyl-1H-pyrazol-3- 7.16 (m, 1H), 8.03 (m, 2H) 11619-11640ylamino)pyrimidine  83 5-Bromo-2-(3- 2.15 (s, 3H), 4.6 (s, 2H), 426 Meth1 Meth phenylisoxazol-5- 6.0-6.5 (br s, 1H), 6.75 (br s, 1H), 56ylmethylamino)-4-(5- 7.44 (m, 3H), 7.8 (m, 2H), 8.05 (s, 1H)methyl-1H-pyrazol-3- ylamino)pyrimidine  84 5-Bromo-2-[4-(pyrid-2- 2.11(s, 3H), 4.61 (s, 2H), 6.1 (br 437 Meth 1 Meth yl)pyrid-2- s, 1H), 7.42(t, 1H), 7.98 (m, 4H), 100 ylmethylamino]-4-(5- 8.00 (s, 1H), 8.60 (d,1H), 8.67 (d, methyl-1H-pyrazol-3- 1H) ylamino)pyrimidine  855-Bromo-2-[5-(pyrid-2- 2.12 (s, 3H), 4.54 (s, 2H), 6.20 (br 437 Meth 1Meth yl)pyrid-3- s, 1H), 7.39 (t, 1H), 7.89 (m, 2H), 102ylmethylamino]-4-(5- 8.02 (s, 1H), 8.37 (s, 1H), 8.55 (s,methyl-1H-pyrazol-3- 1H), 8.69 (d, 1H), 9.08 (s, 1H) ylamino)pyrimidine 86 5-Chloro-2-[5-(pyrid-2- 2.12 (s, 3H), 4.54 (s, 2H), 6.20 (br 393Meth Meth yl)pyrid-3- s, 1H), 7.89 (m, 2H), 7.94 (s, 1H), 10 102ylmethylamino]-4-(5- 8.38 (s, 1H), 8.56 (s, 1H), 8.67 (d,methyl-1H-pyrazol-3- 1H), 9.08 (s, 1H) ylamino)pyrimidine  875-Bromo-2-(6- 2.15 (s, 3H), 4.48 (s, 2H), 5.85 (br 394 Meth 1 Methchloropyrid-2- s, 1H), 7.25 (d, 1H), 7.35 (d, 1H), 94ylmethylamino)-4-(5- 7.75 (t, 1H), 8.00 (s, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine  88 5-Bromo-2-(3- 2.17 (s, 3H), 2.30 (s, 3H), 4.55(s, 374 Meth 1 Meth methylpyrid-2- 2H), 6.20 (br s, 1H), 7.20 (t, 1H),97 ylmethylamino)-4-(5- 7.55 (d, 1H), 8.03 (s, 1H), 8.35 (d,methyl-1H-pyrazol-3- 1H) ylamino)pyrimidine  89 5-Bromo-2-(6- 2.12 (s,3H), 2.45 (s, 3H), 4.48 (s, 374 Meth 1 Meth methylpyrid-2- 1H), 6.00 (brs, 1H), 7.08 (d, 2H), 95 ylmethylamino)-4-(5- 7.55 (t, 1H), 8.00 (s, 1H)methyl-1H-pyrazol-3- ylamino)pyrimidine  90 5-Bromo-2-(5,6- 2.10 (s,3H), 2.18 (s, 3H), 2.40 (s, 388 Meth 1 Meth dimethylpyrid-2- 3H), 4.45(s, 2H), 6.10 (br s, 1H), 96 ylmethylamino)-4-(5- 7.03 (d, 1H), 7.45 (d,1H), 7.98 (s, methyl-1H-pyrazol-3- 1H) ylamino)pyrimidine  915-Chloro-2-(3- 1.20 (d, 6H), 2.15 (s, 3H), 348 Meth methylisoxazol-5-2.88 (m, 1H), 4.50 (s, 2H), 6.08 (s, 19 ylmethylamino)-4-(5- 1H), 6.30(s, 1H), 7.95 (s, 1H) isopropyl-1H-pyrazol-3- ylamino)pyrimidine  925-Bromo-4-(5-methyl- 1.45 (d, 3H), 2.15 (s, 3H), 5.00 (s, 374 Meth 1Meth 1H-pyrazol-3-ylamino)- 1H), 5.95 (br s, 1H), 7.18 (m, 1H), 912-[1-(pyrid-2- 7.35 (d, 1H), 7.68 (t, 1H), 7.95 (s, yl)ethylamino]- 1H),8.50 (d, 1H) pyrimidine  93 5-Bromo-4-(5-methyl- 1.45 (d, 3H), 2.17 (s,3H), 4.98 (s, 374 Meth 1 Meth 1H-pyrazol-3-ylamino)- 1H), 6.00 (br s,1H), 7.30 (m, 1H), 90 2-[1-(pyrid-3- 7.75 (d, 1H), 7.93 (s, 1H), 8.38(d, yl)ethylamino]- 1H), 8.55 (s, 1H) pyrimidine  945-Chloro-4-(5-methyl- 1.45 (d, 3H), 2.18 (s, 3H), 5.00 (s, 330 Meth Meth1H-pyrazol-3-ylamino)- 1H), 6.00 (br s, 1H), 7.33 (m, 1H), 10 902-[1-(pyrid-3- 7.75 (d, 1H), 7.90 (s, 1H), yl)ethylamino]- 8.38 (m, 1H),8.56 (s, 1H) pyrimidine  95 5-Bromo-4-(5-methyl- 0.88 (t, 3H), 1.85 (m,2H), 2.18 (s, 388 Meth 1 Meth 1H-pyrazol-3-ylamino)- 3H), 4.80 (s, 1H),6.00 (br s, 1H), 92 2-[1-(pyrid-2- 7.20 (m, 1H), 7.33 (d, 1H),yl)propylamino]- 7.69 (t, 1H), 7.95 (s, 1H), 8.45 (d, 1H) pyrimidine  965-Chloro-4-(5-methyl- 0.87 (t, 3H), 1.80 (m, 2H), 2.19 (s, 344 Meth Meth1H-pyrazol-3-ylamino)- 3H), 4.83 (s, 1H), 6.00 (br s, 1H), 10 922-[1-(pyrid-2- 7.18 (m, 1H), 7.33 (d, 1H), yl)propylamino]- 7.67 (t,1H), 7.87 (s, 1H), 8.47 (d, 1H) pyrimidine  97 5-Bromo-4-(5-methyl- 0.85(t, 3H), 1.73 (m, 2H), 2.15 (s, 388 Meth 1 Meth 1H-pyrazol-3-ylamino)-3H), 4.73 (s, 1H), 6.00 (br s, 1H), 93 2-[1-(pyrid-3- 7.30 (m, 1H), 7.70(d, 1H), yl)propylamino]- 7.93 (s, 1H), 8.35 (d, 1H), 8.50 (s, 1H)pyrimidine  98 5-Chloro-4-(5-methyl- 0.89 (t, 3H), 1.77 (m, 2H), 2.20(s, 344 Meth Meth 1H-pyrazol-3-ylamino)- 3H), 4.78 (s, 1H), 6.05 (br s,1H), 10 93 2-[1-(pyrid-3- 7.30 (t, 1H), 7.75 (d, 1H), 7.85 (s,yl)propylamino]- 1H), 8.38 (d, 1H), 8.52 (s, 1H) pyrimidine  995-Bromo-2-(3- 1.19 (s, 3H), 4.43 (d, 2H), 6.02 (br 440 Meth 1 WObromopyrid-5- s, 1H), 7.65 (t, 1H), 7.90 (s, 1H), 99/ylmethylamino)-4-(5- 8.04 (s, 1H), 8.46 (s, 1H), 8.55 (s, 00385methyl-1H-pyrazol-3- 1H), 12.10 (br s, 1H) ylamino)pyrimidine 100¹¹5-Bromo-2-[2-(1- 1.48 (s, 9H), 3.07 (t, 2H), 3.71 (s, 418 MethTetrahedron methylpyrrol-2- 3H), 3.80 (m, 2H), 6.07 (s, 1H), 12 1999yl)ethylamino]-4-(5-tert- 6.13 (t, 1H), 6.74 (m, 2H), 8.17 (s, (55),butyl-1H-pyrazol-3- 1H) 11619-11640 ylamino)pyrimidine 101 5-Bromo-2-[2-1.26 (s, 9H), 2.92 (m, 2H), 3.62 (t, 417 Meth J Am (pyrimidin-5- 2H),6.38 (s, 1H), 8.35 (s, 1H), 12 Chem yl)ethylamino]-4-(5-tert- 8.73 (s,2H), 9.14 (s, 1H) Soc, butyl-1H-pyrazol-3- 1950, ylamino)pyrimidine 72,3539¹² 102 5-Chloro-2-(pyrid-3- 0.84 (t, 3H), 1.50 (m, 2H), 344 Methylmethylamino)-4-(5- 2.45 (m, 2H), 4.46 (s, 2H), 6.18 (br s, 16propyl-1H-pyrazol-3- 1H), 7.30 (t, 1H), 7.67 (d, 1H), ylamino)pyrimidine7.91 (s, 1H), 8.38 (d, 1H), 8.48 (s, 1H) 103 5-Chloro-4-(5-isopropyl-1.13 (d, 6H), 2.84 (m, 1H), 344 Meth 1H-pyrazol-3-ylamino)- 4.47 (s,2H), 6.24 (br s, 1H), 7.29 (t, 19 2-(pyrid-3- 1H), 7.65 (d, 1H), 7.92(s, 1H), ylmethylamino)- 8.39 (d, 1H), 8.49 (s, 1H) pyrimidine 1045-Bromo-2-[3- 2.17 (s, 3H), 3.84 (s, 3H), 4.59 (s, 408 Meth 1 Meth(methoxycarbonyl)isoxazol- 2H), 6.21 (br s, 1H), 6.58 (s, 1H), 74¹³5-ylmethylamino]-4- 8.03 (s, 1H) (5-methyl-1H-pyrazol-3-ylamino)pyrimidine 105 5-Bromo-2-[3- 1.86 (m, 4H), 2.18 (s, 3H), 3.44(t, 447 Meth 1 Meth (pyrrolidin-1- 2H), 3.57 (t, 2H), 4.58 (s, 2H), 78ylcarbonyl)isoxazol-5- 6.20 (br s, 1H), 6.44 (s, 1H),ylmethylamino]-4-(5- 8.04 (s, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine 106 5-Bromo-2-[3- 2.17 (s, 3H), 4.40 (s, 2H), 4.50(s, 380 Meth 1 Meth (hydroxymethyl)isoxazol- 2H), 6.17 (s, 1H), 6.28 (brs, 1H), 76 5-ylmethylamino]-4-(5- 8.02 (s, 1H) methyl-1H-pyrazol-3-ylamino)pyrimidine ¹Heated for 12 hours. ²Heated for 24 hours. ³Reactiontreated with 2M NH₃/MeOH to pH 9. Precipitate was filtered and washedwith distilled water and diethyl ether. ⁴No aqueous work-up, productprecipitates from DCM. ⁵No chromatography necessary. ⁶500 MHz (393 K).⁷NMR run with no d4 acetic acid. ⁸NMR run at 373 K/400 MHz. ⁹NMR runwith no d4 acetic acid at 343 K. ¹⁰NMR: Trifluorodeuterated aceticacid-d₁ use in place of acetic aicd-d₄. ¹¹NMR run in CD₃OD. ¹²Compoundcould be prepared by the procedure described in this paper. ¹³Esterexchange with the methanol used in the chromatography occurred.

Example 1075-Bromo-2-(3-carbamoylisoxazol-5-ylmethylamino)-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine

5-Bromo-2-[3-(methoxycarbonyl)isoxazol-5-ylmethylamino]-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine(Example 104; 50 mg, 0.11 mmol) was suspended in 7N methanolic ammonia(5 ml) and stirred at ambient temperature for 18 hours. The volatileswere removed by evaporation and the residue was triturated withDCM/diethyl ether (50:50) and the product collected by filtration togive the title compound (35 mg, 76%). NMR (DMSO): 2.18 (s, 3H), 4.57 (d,2H), 6.28 (br s, 1H), 6.50 (s, 1H), 7.72 (s, 2H), 8.01 (s, 1H), 8.05 (s,1H), 12.06 (s, 1H); m/z 393 (MH)⁺.

Preparation of Starting Materials:—

The starting materials for the examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1 5-Bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine

A solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol),3-amino-5-methyl-1H-pyrazole (6.0 g, 62 mmol) andN,N-diisopropylethylamine (9.20 ml, 53 mmol) in 1-butanol (80 ml) washeated at 85° C. for 12 hours. The mixture was allowed to cool toambient temperature and the resulting precipitate collected byfiltration. The solid product was washed with ethanol and dried to givethe sub-titled compound (10.8 g, 85%). ¹H NMR (DMSO): δ 2.23 (s, 3H),6.23 (s, 1H), 8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); MS: m/z 290(MH)⁺.

Method 2 2-Oxobutylnitrile

Acetonitrile (13.7 ml, 260 mmol) was added to a suspension of sodiumhydride (10.4 g of a 60% suspension in mineral oil, 260 mmol) in ethylpropionate (22.3 g, 220 mmol) and anhydrous 1,4-dioxane (200 ml) atambient temperature. The mixture was heated at 100° C. for 12 hours andthen allowed to cool. Water was added, the mixture adjusted to pH 2.0with concentrated hydrochloric acid and extracted with DCM. The extractswere combined dried (MgSO₄) and the volatiles removed by evaporation.The residue was purified by column chromatography on silica gel elutingwith DCM to give the title compound (20 g, 94%) as an oil. NMR (CDCl₃):1.10 (t, 3H), 2.65 (q, 2H), 3.50 (s, 2H).

Methods 3-5

The following compounds were prepared by the procedure of Method 2 usingthe appropriate starting materials.

Method Method 3 2-Cyclopropyl-2-oxoethylnitrile 4 2-Oxopentylnitrile 52-Oxo-3-methylbutylnitrile

Method 6 3-Amino-5-ethyl-1H-pyrazole

Hydrazine monohydrate (11.3 g, 230 mmol) was added to a solution of3-oxobutyronitrile (Method 2; 20.0 g, 210 mmol) in ethanol (50 ml) andthe mixture heated at 70° C. for 12 hours. The volatiles were removed byevaporation and the residue was purified by column chromatography onsilica gel eluting with DCM/methanol (90:10) to give the title compoundas an oil. (10.2 g, 44%). NMR (DMSO): 1.10 (t, 3H), 2.40 (q, 2H), 5.15(s, 1H); m/z 112 (MH)⁺.

Methods 7-9

The following compounds were prepared by the procedure of Method 6 usingthe appropriate starting materials.

Method Compound SM 7 3-Amino-5-cyclopropyl-1H-pyrazole Method 3 83-Amino-5-propyl-1H-pyrazole Method 4 9 3-Amino-5-isopropyl-1H-pyrazoleMethod 5

Method 10 2,5-Dichloro-4-(5-methyl-1H-pyrrazol-3-ylamino)pyrimidine

A solution of 2,4,5-trichloropyrimidine (6.0 g, 32.6 mmol),3-amino-5-methyl-1H-pyrrazole (3.18 g, 32.7 mmol) andN,N-diisopropylethylamine (6.30 ml, 36.2 mmol) in 1-butanol (50 ml) washeated at 100° C. for 2 hours. The volatiles were removed by evaporationand the residue was triturated with DCM to afford the title compound(5.7 g, 72%) as a white solid. NMR (DMSO): 2.23 (s, 3H), 6.23 (s, 1H),8.39 (s, 1H), 9.21 (s, 1H), 12.27 (s, 1H); m/z 290 (MH)⁺.

Methods 11-21

The following compounds were prepared by the procedure of Method 10using the appropriate starting materials.

Meth Compound SM 115-Bromo-2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 712 5-Bromo-2-chloro-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 132,5-Dichloro-4-(5-tert-butyl-1H-pyrazol-3-ylamino)pyrimidine 145-Bromo-2-chloro-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine Meth 6 154-(5-Methyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine 162,5-Dichloro-4-(5-propyl-1H-pyrazol-3-ylamino)pyrimidine Meth 8 172,5-Dichloro-4-(5-ethyl-1H-pyrazol-3-ylamino)pyrimidine Meth 6 185-Bromo-4-(5-propyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine Meth 8 192,5-Dichloro-4-(5-isopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 9 202,5-Dichloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine Meth 7 215-Bromo-4-(5-isopropyl-1H-pyrazol-3-ylamino)-2-chloropyrimidine Meth 9

Method 22 α-Chlorobenzaldehyde oxime

N-chlorosuccinimide (5.50 g, 41.3 mmol) was added in portions to asolution of benzaldehyde oxime (5.0 g, 41.3 mmol) in DMF (34 ml) suchthat the temperature did not rise above 35° C. The mixture was stirredat ambient temperature for 2 hours and then cooled with an ice bath.Water was added and the aqueous mixture extracted with ether. Theorganics were combined, washed with water and brine, dried (MgSO₄) andthe solvent removed by evaporation to give the title compound (6.43 g,100%) as an oil. NMR (CDCl₃): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H).

Methods 23-33

The following compounds were prepared by the procedure of Method 22using the appropriate starting materials.

Method Compound SM 23 1-chloro-2-methylpropylaldehyde oxime 24α-Chloro-2-methoxybenzaldehyde oxime 25 α-Chloro-2-chlorobenzaldehydeoxime Method 36 26 α-Chloro-2-fluorobenzaldehyde oxime Method 37 27α-Chloro-2-trifluoromethoxybenzaldehyde Method 38 oxime 28α-Chloro-2-ethoxybenzaldehyde oxime Method 39 29α-Chloro-2-trifluoromethylbenzaldehyde oxime Method 40 30α-Chloro-2-methylbenzaldehyde oxime Method 41 31α-Chloro-2-bromobenzaldehyde oxime 32α-Chloro-2-methoxypyrid-3-ylcarbaldehyde J. Chem. Soc. oxime PerkinTrans 1 1990 2409-15. 33 α-Chloro-3-methoxybenzaldehyde oxime Method 35

Method 34

α-Chloro-pyrid-3-ylcarbaldehyde oxime was Prepared According to theMethod Described in Tetrahedron 2000, 56, 1057-1064.

Method 35 3-Methoxybenzaldehyde oxime

A solution of hydroxylamine hydrochloride (10 g, 0.144 mol) in distilledwater (20 ml) was added to 20% (w/v) aqueous sodium hydroxide solution(28 ml). 3-Methoxybenzaldehyde (14 ml, 0.12 mol) was added in oneportion and the mixture was stirred for 2 hours at 0-5° C. The mixturewas adjusted to pH7 and extracted with dichloromethane. The extractswere combined, dried (MgSO₄) and the solvent removed by evaporation togive the title compound (18.7 g, 100%) as a colourless oil. NMR (CDCl₃):3.8 (s, 3H), 6.9 (m, 1H), 7.1 (m, 2H), 7.15 (m, 1H), 8.1 (s, 1H), 8.6(br s, 1H).

Methods 36-42

The following compounds were prepared by the procedure of Method 35using the appropriate starting materials.

Method Compound 36 2-chlorobenzaldehyde oxime 37 2-fluorobenzaldehydeoxime 38 2-trifluoromethoxybenzaldehyde oxime 39 2-ethoxybenzaldehydeoxime 40 2-trifluoromethylbenzaldehyde oxime 41 2-methylbenzaldehydeoxime 42 2-iodobenzaldehyde oxime

Method 43 5-(tert-Butoxycarbonylaminomethyl)-3-phenylisoxazole

A solution of α-chlorobenzaldehyde oxime (Method 22; 1 g, 6.4 mmol) inTHF (13 ml) was added dropwise to a solution ofN-tert-butoxycarbonyl-propargylamine (0.5 g, 3.2 mmol) and triethylamine(0.9 ml, 6.4 mmol) in THF (25 ml) cooled with an ice bath. The mixturewas allowed to warm to ambient temperature and stirred for 2 days. Thevolatiles were removed by evaporation and the residue dissolved in DCM.The solution was washed with water and brine, dried (MgSO₄) and thesolvent removed by evaporation. The residue was triturated withisohexane/ether (9:1) and collected by filtration to give the titlecompound (473 mg, 54%). NMR (CDCl₃) 1.45 (s, 9H), 4.45 (d, 2H), 5.10(bs, 1H), 6.5 (s, 1H), 7.42 (m, 3H), 7.8 (m, 2H).

Methods 44-55

The following compounds were prepared by the procedure of Method 43using the appropriate starting materials.

Meth Compound SM 445-(tert-Butoxycarbonylaminomethyl)-3-isopropylisoxazole Meth 23 455-(tert-Butoxycarbonylaminomethyl)-3-(2-methoxyphenyl)isoxazole Meth 2446 5-(tert-Butoxycarbonylaminomethyl)-3-(2-chlorophenyl)isoxazole Meth25 47 5-(tert-Butoxycarbonylaminomethyl)-3-(2-fluorophenyl)isoxazoleMeth 26 48 5-(tert-Butoxycarbonylaminomethyl)-3-(2- Meth 27trifluoromethoxyphenyl)isoxazole 495-(tert-Butoxycarbonylaminomethyl)-3-(2-ethoxyphenyl)isoxazole Meth 2850 5-(tert-Butoxycarbonylaminomethyl)-3-(2- Meth 29trifluoromethylphenyl)isoxazole 515-(tert-Butoxycarbonylaminomethyl)-3-(2-methylphenyl)isoxazole Meth 3052 5-(tert-Butoxycarbonylaminomethyl)-3-(2-bromophenyl)isoxazole Meth 3153 5-(tert-Butoxycarbonylaminomethyl)-3-(2-methoxypyrid-3-yl)isoxazoleMeth 32 545-(tert-Butoxycarbonylaminomethyl)-3-(3-methoxyphenyl)isoxazole Meth 3355 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-3-yl)isoxazole Meth 34

Method 56 5-Aminomethyl-3-phenylisoxazole

Trifluoroacetic acid (1.7 ml, 2.6 mmol) was added dropwise to a solutionof 5-(tert-butoxycarbonylaminomethyl)-3-phenylisoxazole (Method 43; 473mg, 1.73 mmol) in DCM (8 ml) cooled in an ice bath. The mixture waswarmed to ambient temperature and stirred for 18 hours and the volatilesremoved by evaporation. The residue was triturated with ether to givethe title compound (427 mg, 86%). NMR (DMSO) 4.33 (s, 2H), 7.1 (s, 1H),7.5 (m, 3H), 7.8 (m, 2H), 8.6 (br s, 3H).

Methods 57-68

The following compounds were prepared by the procedure of Method 56using the appropriate starting materials.

Method Compound Method 57 5-Aminomethyl-3-isopropylisoxazole Method 4458 5-Aminomethyl-3-(2-methoxyphenyl)isoxazole Method 45 595-Aminomethyl-3-(2-chlorophenyl)isoxazole Method 46 605-Aminomethyl-3-(2-fluorophenyl)isoxazole Method 47 615-Aminomethyl-3-(2-trifluoromethoxyphenyl)- Method 48 isoxazole 625-Aminomethyl-3-(2-ethoxyphenyl)isoxazole Method 49 635-Aminomethyl-3-(2-trifluoromethylphenyl)- Method 50 isoxazole 645-Aminomethyl-3-(2-methylphenyl)isoxazole Method 51 655-Aminomethyl-3-(2-bromophenyl)isoxazole Method 52 665-Aminomethyl-3-(2-methoxypyrid-3-yl)isoxazole Method 53 675-Aminomethyl-3-(3-methoxyphenyl)isoxazole Method 54 685-Aminomethyl-3-(pyrid-3-yl)isoxazole Method 55

Method 69 5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-2-yl)isoxazole

Sodium hypochlorite (16 ml of a 14% w/v aqueous solution, 29.5 mmol) wasadded dropwise to a solution of 2-pyridinealdoxime (2 g, 16.4 mmol) andN-tert-butoxycarbonyl-propargylamine (5.6 g, 36.1 mmol) in DCM (30 ml)cooled in an ice bath. The mixture was stirred vigorously and allowed towarm to ambient temperature and stirred for 18 hours. The aqueous layerwas separated and extracted with DCM. The combined organic extracts werecombined, dried (MgSO₄) and the solvent removed by evaporation. Theresidue was purified by column chromatography on silica gel eluting withdiethyl ether/isohexane (1:1) to give the title compound (1.93 g, 43%).NMR (CDCl₃) 1.45 (s, 9H), 4.5 (m, 2H), 5.03 (bs, 1H), 6.8 (s, 1H), 7.35(m, 1H), 7.8 (m, 1H), 8.05 (d, 1H), 8.67 (m, 1H).

Method 70 5-Aminomethyl-3-(pyrid-2-yl)isoxazole

5-(tert-Butoxycarbonylaminomethyl)-3-(pyrid-2-yl)isoxazole (Method 69)was treated as described in Method 56 to give5-aminomethyl-3-(2-pyridyl)isoxazole. NMR (DMSO) 4.38 (s, 2H), 7.1 (s,1H), 7.5 (m, 1H), 7.95 (m, 2H), 8.65 (br s, 3H), 8.7 (m, 1H).

Method 71 3-Methyl-5-(1-phthalamidoethyl)isoxazole

A solution of triethylamine (0.35 ml, 2.5 mmol) in toluene (15 ml) wasadded dropwise to a solution of phenylisocyanate (5.43 ml, 50 mmol),nitroethane (2.15 ml, 30 mmol) and N-(but-1-yn-3-yl)phthalamide (5.0 g,25 mmol) in toluene (65 ml) at ambient temperature. The mixture wasstirred for 18 hours, filtered and the volatiles removed by evaporation.The residue was triturated with ether and the product collected byfiltration to give the title compound (5.35 g, 89%). NMR (CDCl₃): 1.88(d, 3H), 2.27 (s, 3H), 5.60 (q, H), 6.11 (s, H), 7.69-7.75 (m, 2H),7.79-7.85 (m, 2H); m/z 257 (MH)⁺.

Method 72 5-(1-aminoethyl)-3-methylisoxazole

A mixture of the 3-methyl-5-(1-phthalamidoethyl)isoxazole (Method 71;3.55 g, 13.9 mmol), hydrazine monohydrate (0.75 ml, 15.3 mmol) andethanol (50 ml) was heated at reflux for 4 hours. The mixture wasallowed to cool to ambient temperature and glacial acetic acid (8.8 ml,153 mmol) added, the mixture then heated at reflux for 2 hours. Themixture was allowed to cool to ambient temperature and the mixtureneutralized with 50% aqueous sodium hydroxide solution, diluted withwater and extracted with DCM, and the combined extracts washed withwater followed by brine. The organics were separated, dried (MgSO₄) andthe solvent removed by evaporation. The residue was dissolved in ethanoland treated with an excess of 1N ethereal hydrogen chloride, thevolatiles removed by evaporation to give the title compound (1.52 g,87%). NMR (DMSO): 1.46 (dd, 3H), 2.20 (m, 3H), 4.39 (q H), 6.38 (s, 1H),6.60 (br s, 3H); m/z 127 (MH)⁺.

Method 733-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole

A solution of ethyl chlorooximidoacetate (10 g, 66 mmol) in THF (200 ml)was added dropwise over 3 hours to a mixture ofN-(tert-butyloxycarbonyl)propargylamine (20.5 g, 13 mmol) andtriethylamine (11.2 ml, 80 mmol) in tetrahyrofuran (100 ml). The mixturewas stirred at ambient temperature for 18 hours and then the volatileswere removed by evaporation. The residue was dissolved in DCM and washedwith water followed by brine. The organics were separated, dried (MgSO₄)and the solvent removed by evaporation. The residue was purified bycolumn chromatography on silica gel eluting with isohexane/diethyl ether(80:20 then 50:50) to give the title compound (10.6 g, 60%). NMR (DMSO):1.3 (t, 3H), 1.38 (s, 9H), 4.35 (m, 2H), 6.62 (s, 1H), 7.55 (s, 1H); m/z269 (M-H)⁻.

Method 74 3-Ethoxycarbonyl-5-aminomethylisoxazole

Trifluoroacetic acid (2.1 ml, 29 mmol) was added to a solution of3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole(Method 73; 790 mg, 2.9 mmol) in DCM (15 ml). The mixture was stirred atambient temperature for 4 hours then the volatiles removed byevaporation. The residue was triturated with diethyl ether to give thetitle compound (763 g, 93%). NMR (DMSO): 1.31 (t, 3H), 4.37 (m, 2H),6.97 (s, 1H), 8.64 (s, 3H); m/z 171 (MH)⁺.

Method 753-Hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole

Sodium borohydride (610 mg, 16 mmol) was added in portions to a solutionof 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole(Method 73; 1.62 g, 6 mmol) in ethanol (15 ml) at 0° C. under a nitrogenatmosphere. The mixture was stirred at ambient temperature for 4 hoursthen quenched with saturated aqueous sodium hydrogen carbonate solution.The mixture was extracted with EtOAc and the organics washed with brinethen dried (MgSO₄). The solvent was removed by evaporation to give thetitle compound (1.25 g, 91%). NMR (DMSO): 1.38 (s, 9H), 4.21 (d, 2H),4.44 (s, 2H), 5.40 (br s, 1H), 6.21 (s, 1H), 7.49 (br s, 1H); m/z 229(MH)⁺.

Method 76 3-Hydroxymethyl-5-aminomethylisoxazole

Trifluoroacetic acid (4 ml, 54 mmol) was added to a solution of3-hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole(Method 75; 1.25 g, 5.4 mmol) in DCM (40 ml). The mixture was stirred atambient temperature for 18 hours then the volatiles removed byevaporation. The residue was purified by chromatography on a SCX-2column (50 g) eluting with methanol then 7N ammonia in methanol to givethe title compound (676 mg, 96%). NMR (DMSO): 1.97 (br s, 2H), 3.76 (s,2H), 4.44 (s, 2H), 5.38 (s, 1H), 6.26 (s, 1H).

Method 773-(Pyrrolidin-1-ylcarbonyl)-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole

3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole(Method 73; 500 mg, 1.85 mmol) was dissolved in pyrrolidine (4 ml) andthe mixture heated for 3 hours at 85° C. The volatiles were removed byevaporation and the residue was triturated with diethyl ether to givethe title compound (432 mg, 79%) as a white solid. NMR (DMSO): 1.38 (s,9H), 1.85 (m, 4H), 3.50 (t, 2H), 3.62 (t, 2H), 4.29 (d, 2H), 6.47 (1H),7.53 (s, 1H); m/z 240 (M-C₄H₈)⁺.

Method 78 3-(Pyrrolidin-1-ylcarbonyl)-5-aminomethyl]isoxazole

3-(Pyrrolidin-1-ylcarbonyl)-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole(Method 77) was deprotected as described in Method 74 to give the titlecompound as its trifluoroacetate salt (428 mg, 95%). NMR (DMSO): 1.88(m, 4H), 3.49 (t, 2H), 3.63 (t, 2H), 4.35 (s, 2H), 6.83 (s, 1H), 8.58(s, 3H); m/z 196 (MH)⁺.

Method 795-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole

2-Iodobenzaldehyde oxime (Method 42) was treated as described in Methods22 and 43 to give the title compound.

Method 805-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-cyanophenyl)isoxazole

Copper (I) cyanide (2.49 g, 27.8 mmol), tetra-n-butylammoniumcyanide(1.87 g, 6.95 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.247 g,0.28 mmol) and diphenylphosphinoferrocene (0.619 g, 1.12 mmol) wereadded to a degassed solution of5-[N-(tert-butoxycarbonyl)aminomethyl]-3-(2-iodoophenyl)isoxazole(Method 79; 2.78 g, 6.95 mmol) in 1,4-dioxan (35 ml) under nitrogen. Themixture was heated at reflux for 3 hours, cooled to ambient temperature,diluted with EtOAc and filtered through diatomaceous earth. The filtratewas washed with saturated aqueous sodium hydrogen carbonate solution andbrine, dried (MgSO₄) and the solvent was removed by evaporation. Theresidue was purified by column chromatography on silica gel eluting withEtOAc/isohexanes (15:85 increasing in polarity to 25:75) to give thetitle compound (1.29 g, 62%). NMR (CDCl₃): 1.49 (s, 9H), 4.52 (d, 2H),5.09 (br s, H), 6.81 (s, H), 7.55 (t, H), 7.70 (t, H), 7.79 (d, H), 7.95(d, H); m/z 300 (MH)⁺.

Method 81 5-Aminomethyl-3-(2-cyanophenyl)isoxazole

5-[N-(tert-Butoxycarbonyl)aminomethyl]-3-(2-cyanophenyl)isoxazole(Method 80; 1.28 g, 4.28 mmol) was treated as described in Method 56 togive the title compound (1.34 g, 100%). NMR (DMSO): 4.45 (s, 2H), 7.17(s, H), 7.73 (dd, H), 7.85-7.95 (m, 2H), 8.62 (br s, 3H); m/z 200 (MH)⁺.

Method 823-Methyl-5-{2-[bis-(N-tert-butoxycarbonyl)amino]ethyl}isoxazole

Bis-N-tert-butoxycarbonyl-3-butyne as synthesised in J. Am. Chem. Soc.1987 (109), 2765 (2.2 g, 8.2 mmol), was treated as described in Method71 to give the title compound (0.59 g, 22%). NMR (CDCl₃): 1.49 (s, 18H),2.24 (s, 3H), 3.00 (t, 2H), 3.88 (t, 2H), 5.85 (s, H).

Method 83 3-Methyl-5-(2-aminoethyl)isoxazole

Trifluoroacetic acid (2.5 ml, 3.8 mmol) was added dropwise to a solutionof 3-methyl-5-{2-[bis-(N-tert-butoxycarbonyl)amino]ethyl}isoxazole(Method 82; 0.589 g, 1.8 mmol) in DCM (10 ml) cooled at 0° C. Themixture was allowed to warm to ambient temperature and stirred for 48hours. The volatiles were removed by evaporation and the residue waspurified by chromatography on a SCX-2 ion exchange column eluting withmethanol and then 7 N ammonia in methanol. The purified product wastreated with an excess of 1.0M ethereal hydrogen chloride (3.5 ml) togive the title compound as its hydrochloride salt (0.24 g, 82%). NMR(DMSO) freebase: 2.18 (s, 3H), 2.71-2.79 (m, 2H), 2.80-2.88 (m, 2H),6.10 (s, H).

Method 84 3-Azidomethyl-5-methylisoxazole

3-Chloromethyl-5-methylisoxazole (500 mg, 3.8 mmol) and sodium azide(494 mg, 7.6 mmol) were heated in DMF (10 ml) at 60° C. for 6 hours. Thereaction mixture was diluted with water then extracted with EtOAc. Theorganic extracts were dried (MgSO₄) and the volatiles removed byevaporation to give the title compound (387 mg, 73%) as an oil. NMR(DMSO): 2.40 (s, 3H), 4.48 (s, 2H), 6.28 (s, 1H).

Method 85 3-Aminomethyl-5-methylisoxazole

3-Azidomethyl-5-methylisoxazole (Method 84; 384 mg, 2.8 mmol) andpolystyrene polymer supported triphenylphosphine (4.2 g, 4.2 mmol) werestirred together in a mixture of THF (17 ml) and distilled water (0.58ml) for 24 hours. The reaction mixture was filtered, the resin washedwith diethyl ether and then DCM. The combined filtrates were evaporatedand the residue purified on a SCX-2 column eluting with methanolfollowed by 7N methanolic ammonia to give the title compound (211 mg,67%) as an oil. NMR (DMSO): 1.93 (br s, 2H), 2.34 (s, 3H), 3.63 (s, 2H),6.17 (s, 1H).

Method 86 α-Methyl-pyridin-3-ylcarbaldehyde oxime

Hydroxylamine hydrochloride (9.46 g, 136.2 mmol) was added to a solutionof 3-acetylpyridine (11.02 g, 90.7 mmol) in methanol (100 ml) and thereaction mixture heated at reflux for 30 minutes. The volatiles wereremoved by evaporation and the residue dissolved in water. The solutionwas cooled to 0° C. and basified with 2N aqueous sodium hydroxidesolution to pH 12 and the mixture then extracted with EtOAc. Theextracts were combined, washed with saturated brine and dried (Na₂SO₄).The solvent was removed by evaporation to give the title product (11.6g, 94%) as a solid. NMR (DMSO): 2.20 (s, 3H), 7.40 (m, 1H), 8.00 (m,1H), 8.55 (d, 1H), 8.85 (s, 1H) 11.43 (s, 1H). m/z: 137 (MH)⁺.

Methods 87-89

The following compounds were prepared by the procedure of Method 86using the appropriate starting materials.

Method Compound 87 α-Methyl-pyridin-2-ylcarbaldehyde oxime 88α-Ethyl-pyridin-2-ylcarbaldehyde oxime 89α-Ethyl-pyridin-3-ylcarbaldehyde oxime

Method 90 3-(1-Aminoethyl)pyridine

A 50% suspension of rainey nickel in water (1.1 g) was added to asolution of α-methyl-pyridin-3-ylcarbaldehyde oxime (Method 86; 10.6 g,77.9 mmol) and 20% ethanolic ammonia (500 ml) and the reaction mixturehydrogenated with gaseous hydrogen at 40 psi and 40° C. until thetheoretical volume of gas was consumed. The reaction mixture wasfiltered through a layer of diatomaceous earth and the filter pad washedwith water and ethanol. The filtrate was removed by evaporation of givethe title product. (8.05 g, 85%) as an oil. NMR (DMSO): 1.28 (d, 3H),4.05 (m, 1H), 7.33 (t, 1H), 7.75 (d, 1H), 8.40 (d, 1H), 8.55 (s, 1H).m/z: 123 (MH)⁺.

Methods 91-93

The following compounds were prepared by the procedure of Method 90using the appropriate starting materials.

Method Compound SM 91 2-(1-Aminoethyl)pyridine Method 87 922-(1-Aminopropyl)pyridine Method 88 93 3-(1-Aminopropyl)pyridine Method89

Method 94 2-Aminomethyl-6-chloropyridine

A 1M solution of lithium aluminium hydride in THF (2.88 ml, 2.88 mmol)was added dropwise to a solution of 6-chloro-2-cyanopyridine (532 mg,3.84 mmol) in THF (10 ml) at −5° C. under an atmosphere of nitrogen. Themixture was stirred at −5° C. for two hours and the reaction quenched bycareful, sequential addition of water (0.1 ml), 15% aqueous sodiumhydroxide solution (0.1 ml) and then water (0.3 ml). The mixture wasstirred for one hour at 0° C., the insolubles removed by filtration andthe filter pad washed thoroughly with methanol. The resulting solutionwas evaporated and the residue purified by column chromatography onsilica gel eluting with DCM/methanol/ammonia (95:5:0 increasing inpolarity to 90:10:1) to give the title compound. (215 mg, 40%) as anoil. NMR (DMSO): 2.10 (br s, 2H), 3.75 (s, 2H), 7.30 (d, 1H), 7.55 (d,1H), 7.80 (t, 1H).

Methods 95-97

The following compounds were prepared by the procedure of Method 94using the appropriate starting materials.

Method Compound 95 2-Aminomethyl-6-methylpyridine  96¹2-Aminomethyl-5,6-dimethylpyridine 97 2-Aminomethyl-3-methylpyridine ¹SMBioorg. Med. Chem. Lett. 1998, 453-8

Method 98 2-(N-Oxopyridin-4-yl)pyridine

3-Chloroperbenzoic acid (57%-86% active strength) (7.5 g, 43 mmol) wasadded in portions to a solution of 2-(pyridin-4-yl)pyridine (4.78 g,30.6 mmol) in DCM (50 ml) at 0° C. After stirring for 2 hours sodiummetabisulfite was added in portions until all excess peroxide wasdestroyed. The solids were removed by filtration and the filtrate wasbasified with solid potassium carbonate. The mixture was filtered, thefiltrate evaporated and the residue purified by column chromatography onsilica gel eluting with methanol/acetone (10:90) to give the titlecompound (4.2 g, 80%) as a white solid. NMR (DMSO): 7.41 (t, 1H), 7.92(t, 1H), 8.10 (m, 3H), 8.30 (d, 2H), 8.70 (d, 1H); m/z 173 (MH)⁺.

Method 99 2-(2-Cyanopyridin-4-yl)pyridine

Trimethylsilylcyanide (1.9 ml, 14.5 mmol) was added dropwise to asuspension of 2-(N-oxopyridin-4-yl)pyridine (Method 98; 1 g, 5.8 mmol)and triethylamine (1.2 ml, 8.7 mmol) in acetonitrile (5 ml). The mixturewas heated at 110° C. for 18 hours, cooled to ambient temperature thendiluted with aqueous saturated sodium hydrogen carbonate solution. Themixture was extracted with DCM, the extracts dried (MgSO₄) and thevolatiles removed by evaporation. The residue was pre-adsorbed ontosilica and purified by column chromatography on silica gel eluting withhexane:EtOAc (1:1). The purified product was triturated with diethylether to give the title compound (627 mg, 60%) as a white solid. NMR(DMSO): 7.54 (t, 1H), 8.01 (t, 1H), 8.25 (d, 1H), 8.40 (d, 1H), 8.66 (s,1H), 8.77 (d, 1H), 8.87 (d, 1H).

Method 100 2-(2-Aminomethylpyridin-4-yl)pyridine

2-(2-Cyanopyridin-4-yl)pyridine (Method 99; 563 mg, 3.11 mmol) wasdissolved in anhydrous THF (10 ml) under a nitrogen atmosphere and wascooled to 0° C. LiAlH₄ (2.3 ml of a 1M solution in THF, 2.3 mmol) wasadded dropwise and the reaction was stirred at 0° C. for 3 hours. Thereaction was quenched with water (0.1 ml) followed by 15% sodiumhydroxide solution (0.1 ml) then water (0.3 ml). The mixture wasfiltered and the filter pad was washed with methanol. The volatiles wereremoved from the filtrate by evaporation to give the title compound (570mg, 99%) as a gum. m/z 186 (MH)⁺

Method 101 2-(3-Cyanopyridin-5-yl)pyridine

2-(3-Bromopyridin-5-yl)pyridine (2 g, 10.9 mmol) in THF (10 ml) wasadded dropwise to a solution of 2-pyridylzincbromide (22 ml of a 0.5Msolution in THF, 11 mmol) in THF (10 ml) under a nitrogen atmosphere.Tetrakis(triphenylphosphine)palladium(0) (630 mg, 0.54 mmol) was addedand the reaction stirred at ambient temperature for 18 hours. Thereaction was quenched with saturated aqueous ammonium chloride solutionthen the volatiles were removed by evaporation. The residue wassuspended in water then extracted with DCM. The organic extracts werecombined, washed with water then filtered through phase separating paperand the volatiles removed by evaporation. The residue was purified bycolumn chromatography on silica gel eluting with hexane:EtOAc (2:1). Thepurified product was triturated with diethyl ether to give the titlecompound (0.98 g, 50%) as a white solid. NMR (DMSO): 7.47 (t, 1H), 7.97(t, 1H), 8.15 (d, 1H), 8.75 (d, 1H), 8.90 (d, 1H), 9.07 (s, 1H), 9.53(s, 1H); m/z 182 (MH)⁺.

Method 102 2-(3-Aminomethylpyridin-5-yl)pyridine

2-(3-Cyanopyridin-5-yl)pyridine (Method 101; 0.98 g, 5.4 mmol) wasdissolved in a mixture of ethanol (45 ml) and methanol (30 ml).Concentrated hydrochloric acid (1.2 ml) and 10% palladium on carboncatalyst (575 mg) were added and the mixture stirred under an atmosphereof hydrogen for 4 hours. The mixture was filtered through diatomaceousearth, the filter pad washed with ethanol and the volatiles removed fromthe filtrate by evaporation. The crude solid was suspended in a smallvolume of methanol and filtered to give the title compound (794 mg, 66%)as an orange solid. NMR (DMSO): 4.31 (m, 2H) 7.58 (t, 1H), 8.09 (t, 1H),8.24 (d, 1H), 8.78 (d, 1H), 8.89 (bs, 2H), 9.03 (s, 1H), 9.26 (s, 1H),9.43 (s, 1H); m/z 186 (MH)⁺.

Pharmacological Analysis Methods for Detecting Inhibition of Igf-1rKinase Activity and Downstream Signalling and Selectivity Over InsulinReceptor Kinase and Egfr Signalling Abbreviations Used

PBS (PBS/T) is Phosphate buffered saline, pH7.4 (with 0.05% Tween 20)

HEPES is N-[2-Hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]

DTT is dithiothreitol

TMB is tetramethyl benzidine

DMSO is dimethyl sulphoxide

BSA is bovine serum albumin

ATP is adenosine tri-phosphate

DMEM is Dulbecco's modified Eagle's Medium

FBS/FCS is foetal bovine/calf serum

HBSS is Hanks Balanced Salts Solution

HRP is horse-radish peroxidase

SDS is sodium dodecyl sulphate

IGF-I (IGF-1R) is insulin-like growth factor-I (IGF-1 receptor)

EGF is Epidermal growth factor

IGF-1R Kinase Assay a) Protein Cloning, Expression and Purification

A DNA molecule encoding a fusion protein containingglutathione-S-transferase (GST), thrombin cleavage site and IGF-1Rintracellular domain (amino-acids 930-1367) and subsequently referred toas GST-IGFR, was constructed and cloned into pFastBac1 (LifeTechnologies Ltd, UK) using standard molecular biology techniques(Molecular Cloning—A Laboratory Manual, Second Edition 1989; Sambrook,Fritsch and Maniatis; Cold Spring Harbour Laboratory Press).

Production of recombinant virus was performed following themanufacturer's protocol. Briefly, the pFastBac-1 vector containingGST-IGFR was transformed into E. coli DH10Bac cells containing thebaculovirus genome (bacmid DNA) and via a transposition event in thecells, a region of the pFastBac vector containing gentamycin resistancegene and the GST-IGFR expression cassette including the baculoviruspolyhedrin promoter was transposed directly into the bacmid DNA. Byselection on gentamycin, kanamycin, tetracycline and X-gal, resultantwhite colonies should contain recombinant bacmid DNA encoding GST-IGFR.Bacmid DNA was extracted from a small scale culture of several BH10Bacwhite colonies and transfected into Spodoptera frugiperda Sf21 cellsgrown in TC100 medium (Life Technologies Ltd, UK) containing 10% serumusing CellFECTIN reagent (Life Technologies Ltd, UK) following themanufacturer's instructions. Virus particles were harvested bycollecting cell culture medium 72 hrs post transfection. 0.5 mls ofmedium was used to infect 100 ml suspension culture of Sf21s containing1×10⁷ cells/ml. Cell culture medium was harvested 48 hrs post infectionand virus titre determined using a standard plaque assay procedure.Virus stocks were used to infect Sf9 and “High 5” cells at amultiplicity of infection (MOI) of 3 to ascertain expression ofrecombinant GST-IGFR.

The GST-IGFR protein was purified by affinity chromatography onGlutathione-Sepharose followed by elution with glutathione. Briefly,cells were lysed in 50 mM HEPES pH 7.5 (Sigma, H3375), 200 mM NaCl(Sigma, S7653), Complete Protease Inhibitor cocktail (Roche, 1 873 580)and 1 mM DTT (Sigma, D9779), hereinafter referred to as lysis buffer.Clarified lysate supernatant was loaded through a chromatography columnpacked with Glutathione Sepharose (Amersham Pharmacia Biotech UK Ltd.).Contaminants were washed from the matrix with lysis buffer until the UVabsorbance at 280 nm returned to the baseline. Elution was carried outwith lysis buffer containing 20 mM reduced glutathione (Sigma, D2804)and fractions containing the GST fusion protein were pooled and dialysedinto a glycerol-containing buffer comprising 50 mM HEPES, pH 7.5, 200 mMNaCl, 10% glycerol (v/v), 3 mM reduced glutathione and 1 mM DTT.

b) Kinase Activity Assay

The activity of the purified enzyme was measured by phosphorylation of asynthetic poly GluAlaTyr (EAY) 6:3:1 peptide (Sigma-Aldrich Company Ltd,UK, P3899) using an ELISA detection system in a 96-well format

b.i) Reagents Used Stock Solutions

200 mM HEPES, pH 7.4 stored at 4° C. (Sigma, H3375) 1M DTT stored at−20° C. (Sigma, D9779) 100 mM Na₃VO₄ stored at 4° C. (Sigma, S6508) 1MMnCl₂ stored at 4° C. (Sigma, M3634)  1 mM ATP stored at −20° C. (Sigma,A3377) Neat Triton X-100 stored at room (Sigma, T9284) temperature  10mg/ml BSA stored at 4° C. (Sigma, A7888)

Enzyme Solution

GST-IGF-1R fusion protein at 75 ng/ml in 100 mM HEPES, pH 7.4, 5 mM DTT,0.25 mM Na₃VO₄, 0.25% Triton X-100, 0.25 mg/ml BSA, freshly prepared.

Co-Factor Solution

100 mM HEPES, pH 7.4, 60 mM MnCl₂, 5 mM ATP

Poly EAY Substrate

Sigma substrate poly (Glu, Ala, Tyr) 6:3:1 (P3899)

Made up to 1 mg/ml in PBS and stored at −20° C.

Assay Plates

Nunc Maxisorp 96 well immunoplates (Life Technologies Ltd, UK)

Antibodies

Anti-phosphotyrosine antibody, monoclonal from Upstate BiotechnologyInc., NY, USA (UBI 05-321). Dilute 3 μl in 11 ml PBS/T+0.5% BSA perassay plate.

Sheep-anti-mouse IgG HRP-conjugated secondary antibody from AmershamPharmacia Biotech UK Ltd. (NXA931). Dilute 20 μl of stock into 11 mlPBS/T+0.5% BSA per assay plate.

TMB Solution

Dissolve 1 mg TMB tablet (Sigma T5525) into 1 ml DMSO (Sigma, D8779) inthe dark for 1 hour at room temperature. Add this solution to 9 ml offreshly prepared 50 mM phosphate-citrate buffer pH 5.0+0.03% sodiumperborate [1 buffer capsule (Sigma P4922) per 100 ml distilled water].

Stop solution is 1M H₂SO₄ (Fisher Scientific UK. Cat. No. S/9200/PB08).

Test Compound

Dissolve in DMSO to 10 mM then dilutions in distilled water to give arange from 200 to 0.0026 μM in 1-2% DMSO final concentration in assaywell.

b.ii) Assay Protocol

The poly EAY substrate was diluted to 1 μg/ml in PBS and then dispensedin an amount of 100 μl per well into a 96-well plate. The plate wassealed and incubated overnight at 4° C. Excess poly EAY solution wasdiscarded and the plate was washed (2×PBS/T; 250 μl PBS per well),blotting dry between washes. The plate was then washed again (1×50 mMHEPES, pH 7.4; 250 μl per well) and blotted dry (this is important inorder to remove background phosphate levels). 10 μl test compoundsolution was added with 40 μl of kinase solution to each well. Then 50μl of co-factor solution were added to each well and the plate wasincubated for 60 minutes at room temperature.

The plate was emptied (i.e. the contents were discarded) and was washedtwice with PBS/T (250 μl per well), blotting dry between each wash. 100μl of diluted anti-phosphotyrosine antibody were added per well and theplate was incubated for 60 minutes at room temperature.

The plate was again emptied and washed twice with PBS/T (250 μl perwell), blotting dry between each wash. 100 μl of dilutedsheep-anti-mouse IgG antibody were added per well and the plate was leftfor 60 minutes at room temperature. The contents were discarded and theplate washed twice with PBS/T (250 μl per well), blotting dry betweeneach wash. 100 μl of TMB solution were added per well and the plate wasincubated for 5-10 minutes at room temperature (solution turns blue inthe presence horse radish peroxidase).

Reaction was stopped with 50 μl of H₂SO₄ per well (turns the bluesolution yellow) and the plate was read at 450 nm in Versamax platereader (Molecular Devices Corporation, CA, USA) or similar.

The compounds of the Examples were found to have an IC₅₀ in the abovetest of less than 100 μM.

Inhibition of IGF-Stimulated Cell Proliferation

The construction of murine fibroblasts (NIH3T3) over-expressing humanIGF-1 receptor has been described by Lammers et al (EMBO J, 8,1369-1375, 1989). These cells show a proliferative response to IGF-Iwhich can be measured by BrdU incorporation into newly synthesised DNA.Compound potency was determined as causing inhibition of theIGF-stimulated proliferation in the following assay:

a.i) Reagents Used:

Cell Proliferation ELISA, BrdU (colorimetric) [Boehringer Mannheim(Diagnostics and Biochemicals) Ltd, UK. Cat no. 1 647 229].

DMEM, FCS, Glutamine, HBSS (all from Life Technologies Ltd., UK).

Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UKLtd).

BSA (Sigma, A7888).

Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008176 298, Australia. Cat No. IU 100).

Preparation and Storage of IGF

100 μg of lyophilised IGF was reconstituted in 100 ul of 10 mM HCl.

Add 400 μl of 1 mg/ml BSA in PBS

25 μl aliquots@200 μg/ml IGF-1

Stored at −20° C.

For Assay:

10 μl of stock IGF+12.5 ml growth medium to give 8× stock of 160 ng/ml.

Complete Growth Medium

DMEM, 10% FCS, 2 mM glutamine

Starvation Medium

DMEM, 1% charcoal/dextran stripped FCS, 2 mM glutamine

Test Compound

Compounds are initially dissolved in DMSO to 10 mM, followed bydilutions in DMEM+1% FCS+glutamine to give a range from 100 to 0.0.45 μMin 1-0.00045% DMSO final concentration in assay well

a.ii) Assay Protocol Day 1

Exponentially growing NIH3T3/IGFR cells were harvested and seeded incomplete growth medium into a flat-bottomed 96 well tissue culture gradeplate (Costar 3525) at 1.2×10⁴ cells per well in a volume of 100 μl.

Day 2

Growth medium was carefully removed from each well using a multi-channelpipette. Wells were carefully rinsed three times with 200 μl with HBSS.100 μl of starvation medium was added to each well and the plate wasre-incubated for 24 hours.

Day 3

50 μl of a 4× concentrate of test compound was added to appropriatewells. Cells were incubated for 30 minutes with compound alone beforethe addition of IGF. For cells treated with IGF, an appropriate volume(i.e. 25 μl) of starvation medium was added to make a final volume perwell up to 200 μl followed by 25 μl of IGF-1 at 160 ng/ml (to give afinal concentration of 20 ng/ml). Control cells unstimulated with IGFalso had an appropriate volume (i.e. 50 μl) of starvation medium addedto make final volume per well up to 200 μl. The plate was re-incubatedfor 20 hours.

Day 4

The incorporation of BrdU in the cells (after a 4 h incorporationperiod) was assessed using the BrdU Cell Proliferation Elisa accordingto the manufacturer's protocol.

The compounds of the Examples were found to have an IC₅₀ in the abovetest of less than 50 μM.

Mechanism of Action Assay

Inhibition of IGF-IR mediated signal transduction was determined bymeasuring changes in phosphorylation of IGF-IR, Akt and MAPK (ERK1 and2) in response to IGF-I stimulation of MCF-7 cells (ATCC No. HTB-22). Ameasure of selectivity was provided by the effect on MAPKphosphorylation in response to EGF in the same cell line.

a.i) Reagents Used:

RPMI 1640 medium, RPMI 1640 medium without Phenol Red, FCS, Glutamine(all from Life Technologies Ltd., UK)

Charcoal/Dextran Stripped FBS (HyClone SH30068.02, Perbio Science UKLtd)

SDS (Sigma, L4390)

2-mercaptoethanol (Sigma, M6250)

Bromophenol blue (Sigma, B5525)

Ponceau S (Sigma, P3504)

Tris base (TRIZMA™ base, Sigma, T1503)

Glycine (Sigma, G7403)

Methanol (Fisher Scientific UK. Cat. No. M/3950/21)

Dried milk powder (Marvel™, Premier Brands UK Ltd.)

Human recombinant IGF-1 Animal/media grade (GroPep Limited ABN 78 008176 298, Australia. Cat No. IU 100).

Human recombinant EGF (Promega Corporation, WI, USA. Cat. No. G5021)

Complete Growth Medium

RPMI 1640, 10% FCS, 2 mM glutamine

Starvation Medium

RPMI1640 medium without Phenol Red, 1% charcoal/dextran stripped FCS, 2mM glutamine

Test Compound

Compounds were initially dissolved in DMSO to 10 mM, followed bydilutions in RPMI 1640 medium without Phenol Red+1% FCS+2 mM glutamineto give a range from 100 to 0.0.45 μM in 1-0.00045% DMSO finalconcentration in assay well.

Western Transfer Buffer

50 mM Tris base, 40 mM glycine, 0.04% SDS, 20% methanol

Laemmli Buffer×2:

100 mM Tris-HCl pH6.8, 20% glycerol, 4% SDS

Sample Buffer×4:

200 mM 2-mercaptoethanol, 0.2% bromophenol blue in distilled water.

Primary Antibodies

Rabbit anti-human IGF-1Rβ (Santa Cruz Biotechnology Inc., USA, Cat. Nosc-713)

Rabbit anti-insulin/IGF-1R [pYpY^(1162/1163)] Dual Phosphospecific(BioSource International Inc, CA, USA. Cat No. 44-8041)

Mouse anti-PKBα/Akt (Transduction Laboratories, KY, USA. Cat. No.P67220)

Rabbit anti-Phospho-Akt (Ser473) (Cell Signalling Technology Inc, MA,USA. Cat. No. #9271)

Rabbit anti-p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA.Cat. No. #9102)

Rabbit anti-Phospho p44/p42 MAP kinase (Cell Signalling Technology Inc,MA, USA. Cat. No. #9101)

Mouse anti-actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700)Antibody dilutions

Secondary antibody in Antibody Dilution in PBST PBST IGFR 1:200 with 5%milk Anti-rabbit with 5% milk Phospho-IGFR 1:1000 with 5% milkAnti-rabbit with 5% milk Akt 1:1000 with 5% milk Anti-mouse with 5% milkPhosphoAkt 1:1000 with 5% milk Anti-rabbit with 5% milk MAPK 1:1000 with5% milk Anti-rabbit with 5% milk Phospho-MAPK 1:1000 with 5% milkAnti-rabbit with 5% milk Actin 1:1000 with 5% milk Anti-mouse with 5%milk

Secondary Antibodies

Goat anti-rabbit, HRP linked (Cell Signalling Technology Inc, MA, USA.Cat. No. #7074)

Sheep-anti-mouse IgG HRP-conjugated (Amersham Pharmacia Biotech UK Ltd.Cat. No. NXA931)

Dilute anti-rabbit to 1:2000 in PBST+5% milk

Dilute anti-mouse to 1:5000 in PBST+5% milk

a.ii) Assay Protocol Cell Treatment

MCF-7 cells were plated out in a 24 well plate at 1×10⁵ cells/well in 1ml complete growth medium. The plate was incubated for 24 hours to allowthe cells to settle. The medium was removed and the plate was washedgently 3 times with PBS 2 ml/well. 1 ml of starvation medium was addedto each well and the plate was incubated for 24 hours to serum starvethe cells.

Then 25 μl of each compound dilution was added and the cells andcompound were incubated for 30 minutes at 37° C. After 30 minutesincubation of the compound, 25 μl of IGF (for 20 ng/ml finalconcentration) or EGF (for 0.1 ng/ml final concentration) was added toeach well as appropriate and the cells incubated with the IGF or EGF for5 minutes at 37° C. The medium was removed (by pipetting) and then 100μl of 2× Laemmli buffer was added. The plates were stored at 4° C. untilthe cells were harvested. (Harvesting should occur within 2 hoursfollowing addition of Laemmli buffer to the cells.)

To harvest the cells, a pipette was used to repeatedly draw up and expelthe Laemmli buffer/cell mix and transfer into a 1.5 ml Eppendorf tube.The harvested cell lysates were kept at −20° C. until required. Theprotein concentration of each lysate could be determined using the DCprotein assay kit (Bio-Rad Laboratories, USA, according tomanufacturer's instructions).

Western Blot Technique

Cell samples were made up with 4× sample buffer, syringed with a 21gauge needle and boiled for 5 minutes. Samples were loaded at equalvolumes and a molecular weight ladder on 4-12% Bis-Tris gels (InvitrogenBV, The Netherlands) and the gels were run in an Xcell SureLock™Mini-Cell apparatus (Invitrogen) with the solutions provided andaccording to the manufacturer's instructions. The gels were blotted ontoHybond C Extra™ membrane (Amersham Pharmacia Biotech UK Ltd.) for 1 hourat 30 volts in the Xcell SureLock™ Mini-Cell apparatus, using Westerntransfer buffer. The blotted membranes were stained with 0.1% Ponceau Sto visualise transferred proteins and then cut into strips horizontallyfor multiple antibody incubations according to the molecular weightstandards. Separate strips were used for detection of IGF-1R, Akt, MAPKand actin control.

The membranes were blocked for 1 hour at room temperature in PBST+5%milk solution. The membranes were then placed into 3 ml primary antibodysolution in 4 well plates and the plates were incubated overnight at 4°C. The membranes were washed in 5 ml PBST, 3 times for 5 minutes eachwash. The HRP-conjugated secondary antibody solution was prepared and 5ml was added per membrane. The membranes were incubated for 1 hour atroom temperature with agitation. The membranes were washed in 5 ml PBST,3 times for 5 minutes each wash. The ECL solution (SuperSignal ECL,Pierce, Perbio Science UK Ltd) was prepared and incubated with themembranes for 1 minute (according to manufacturer's instructions),followed by exposure to light sensitive film and development.

The compounds of the Examples were found to have an IC₅₀ in the abovetest of less than 20 μM.

1. A method of treating cancer comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of formula (I):

or pharmaceutically acceptable salt thereof, to a cancer patient withhematopoietic tumors of lymphoid lineage wherein R¹ represents a 5- or6-membered heteroaromatic ring comprising at least one ring heteroatomselected from nitrogen, oxygen, and sulphur, the ring being optionallysubstituted with at least one substituent selected from C₁-C₆alkyl,C₁-C₆alkoxy (each of which may be optionally substituted by at least onesubstituent selected from halogen, amino, hydroxyl, andtrifluoromethyl), halogen, nitro, cyano, —NR⁵R⁶, carboxyl, hydroxyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl,C₁-C₆alkylcarbonylamino, phenylcarbonyl, —S(O)_(m)C₁-C₆alkyl,—C(O)NR⁷R⁸, —SO₂NR^(7a)R^(8a), and an unsaturated 5- to 6-membered ringwhich may comprise at least one ring heteroatom selected from nitrogen,oxygen, and sulphur, the ring itself being optionally substituted withat least one substituent selected from C₁-C₆alkyl, C₁-C₆alkoxy (each ofwhich may be optionally substituted by at least one substituent selectedfrom halogen, amino, hydroxyl, and trifluoromethyl), halogen, nitro,cyano, —NR⁹R¹⁰, carboxyl, hydroxyl, C₂-C₆alkenyl, C₃-C₆cycloalkyl,C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyl, C₁-C₆alkylcarbonylamino,phenylcarbonyl, —S(O)_(n)C₁-C₆alkyl, —C(O)NR¹¹R¹², and—SO₂NR^(11a)R^(12a); m is 0, 1, or 2; n is 0, 1, or 2; R² represents aC₁-C₄alkyl group optionally substituted with at least one substituentselected from halogen, hydroxyl, and C₁-C₃alkoxy; R³ represents halogen;R⁴ represents a 5-membered heteroaromatic ring comprising at least onering heteroatom selected from nitrogen, oxygen, and sulphur, the ringbeing optionally substituted with at least one substituent selected fromC₁-C₆alkyl, C₁-C₆alkoxy (each of which may be optionally substituted byat least one substituent selected from halogen, amino, hydroxyl, andtrifluoromethyl), halogen, nitro, cyano, —NR¹³R¹⁴, carboxyl, hydroxyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl,C₁-C₄alkylcarbonylamino, phenylcarbonyl, —S(O)_(p)C₁-C₄alkyl,—C(O)NR¹⁵R¹⁶, and —SO₂NR^(15a)R^(16a); p is 0, 1, or 2; R⁵ and R⁶ eachindependently represent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R⁵and R⁶ together with the nitrogen atom to which they are attached form a4- to 6-membered saturated heterocycle; R⁷ and R⁸ each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; R^(7a) and R^(8a) each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R^(7a) and R^(8a)together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; R⁹ and R¹⁰ each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; R¹¹ and R¹² each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R¹¹ and R¹²together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; R^(11a) and R^(12a) each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R^(11a) andR^(12a) together with the nitrogen atom to which they are attached forma 4- to 6-membered saturated heterocycle; R¹³ and R¹⁴ each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R¹³ and R¹⁴together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; R¹⁵ and R¹⁶ each independentlyrepresent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, or R¹⁵ and R¹⁶together with the nitrogen atom to which they are attached form a 4- to6-membered saturated heterocycle; and R^(15a) and R^(16a) eachindependently represent hydrogen, C₁-C₄alkyl, or C₃-C₆cycloalkyl, orR^(15a) and R^(16a) together with the nitrogen atom to which they areattached form a 4- to 6-membered saturated heterocycle.
 2. The method ofclaim 1, wherein said patient has a cancer selected from acutelymphocytic leukaemia, B-cell lymphoma, and Burketts lymphoma.
 3. Acompound 2,5-dichloro-4-(5-methyl-1H-pyrrazol-3-ylamino)pyrimidine.